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A PA20023 > Antidepressants > Flashcards

Antidepressants Flashcards

1
Q

What causes mood disorders

A
  1. Genetic factors - Heritability estimates
  2. Neurotransmitter dysfunction
  3. Psychosocial/environmental factors
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2
Q

What are some neurotransmitters that can cause mood disorders

A
  1. monoamines – 5HT, noradrenaline, dopamine
  2. neuroendocrine
  3. neurogenesis
  4. glutamate
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3
Q

What are some Psychosocial/environmental factors that cause mood disorders

A
  1. Life events e.g. marriage breakdown, loss of job

2. Co-morbidity e.g. chronic pain, substance abuse

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4
Q

What is the Aetiology of mood disorders

A
  1. Biological vulnerability- genetic factors, gender
  2. Biological dysfunction in mood circuits
    a) connectivity
    b) transmitter function
    c) regulation
    d) control
  3. Psychosocial stressors- e.g. trauma, illness, bereavement
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5
Q

What are the brain areas involved in mood regulation

A
  1. FC: Frontal cortex (prefrontal and cingulate) - cognitive function, attention
  2. HP: Hippocampus - cognitive function, memory
  3. NAc: Nucleus Accumbens - reward and aversion
  4. Amy: Amygdala - responses to emotional stimuli
  5. HYP: Hypothalamus - sleep, appetite, energy, sex
  6. VTA: Ventral Tegmental Area - Dopamine projections to other areas
  7. DR: Dorsal Raphe nuclei - 5HT (serotonin) input to other areas
  8. LC: Locus Coeruleus - noradrenaline input to other areas.
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6
Q

What are some functional and structural brain changes in depression

A

1, Increased activation of amygdala in depressed patients

2. Reduced metabolism in frontal cortex

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7
Q

How do monoamines control mood

A
  1. Noradrenaline- Alertness, Concentration
  2. Deficit would lead to impaired ability to concentrate
  3. Monoamine about functional deficit
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8
Q

What is the monoamine theory of depression

A
  1. Joseph Schildkraut 1965
  2. depression - a functional deficit of 5HT and/or noradrenaline in the brain
  3. mania - functional excess
  4. originally from observations that reserpine depletes NA/5HT vesicular stores – depression like behaviour
  5. isoniazid used for TB - elevated mood - blocked MAO - didn’t improve TB but did raise patients mood
  6. ECT for psychosis elevated mood – increased amine metabolites
  7. subsequently found tryptophan increased 5HT elevated mood- food sources
  8. tryptophan hydroxylase blockade depresses mood
  9. inhibiting NA synthesis – depresses mood/calms mania
  10. tricyclic antidepressants - developed for psychosis – elevated mood - blocked amine re-uptake
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9
Q

How is Electroconvulsive therapy (ECT) used to treat mood disorders

A
  1. Schizophrenia (doesn’t work) and epilepsy considered mutually exclusive (not true!).
  2. Limited to severe, drug refractory depression- not widely used
  3. Need to have severe depression and drugs not working
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10
Q

Describe how ECT is used for psychosis

A
  1. chemically and electrically induced convulsions for psychosis using electrodes
  2. Meant to reset the brain
  3. ineffective in schizophrenia
  4. elevated mood
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11
Q

Describe ECT is used for depression

A
  1. general anaesthesia
  2. muscle relaxant or block
  3. electrodes bilateral or unilateral
  4. induction of brief tonic-clonic seizure
  5. short lasting (weeks), needs repetition
  6. confusion and memory deficits are issues
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12
Q

What are some antidepressants that have evolved

A
  1. Monoamine oxidase inhibitors
  2. Tricyclic antidepressants
  3. Receptor blockers
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13
Q

What are MAOI and give example of subclass

A
  1. Subtype selective MAOI

2. RIMA

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14
Q

What are different types of Tricyclic antidepressants

A
  1. 5-HT selective SSRIs
  2. NA selective SNRI
  3. Dual acting DA/NA bupropion
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15
Q

What do receptor blockers do and give examples

A
  1. Block range of 5-HT uptakers
  2. Mianserin –> Mirtazapine
  3. Trazodone –> nefazodone
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16
Q

Describe action of MAOI and what are the different targets

A
  1. MAOB (~92%) extraneuronal
  2. MAOA (~7-8%) intraneuronal mitochondrial bound target for antidepressant inhibitors
  3. NA and 5HT preferred substrates for MAOA
  4. DA for MAOB
  5. Elevates monoamines in cytoplasm not vesicles
  6. Spontaneous leakage increases receptor activation
  7. phenelzine, tranylcypromine, iproniazid - irreversible non-specific MAOIs
  8. Renewed interest with reversible MAOA specific blockers eg. moclobemide
17
Q

What are problems with MAOIs

A
  1. To do with cheese reaction
  2. Hypotension (sympathetic block)
  3. Atropine-like effects
  4. Hepatocellular jaundice
  5. Decline in use with concern over safety
  6. Hypertensive crisis (severe increase in blood pressure): tyramine, sympathomimetic amines
  7. Potentiation of drug action e.g. TCAs, pethidine, alcohol
18
Q

What may be a solution that will enable safe use of MAOIs

A
  1. Renewed interest with development of selective and reversible inhibitors of MAO (RIMAs)
  2. Reversible can overcome block and allow some metabolism- safer
19
Q

Describe action of tricyclic antidepressants

A
  1. First generation, still widely used, serious side effects
  2. Block re-uptake of amines by nerve terminals
  3. 5HT=NA&raquo_space;DA
  4. Elevate released amines in synaptic cleft
  5. Can’t be taken out of cleft
  6. Competitive block with natural substrate
  7. Non selective - imipramine, amitryptiline, clomipramine
  8. NA selective - nortyptiline, desipramine
  9. Also block postsynaptic receptors (e.g. muscarinic Ach, histamine, 5HT - side effects
20
Q

What are major side effects of tricyclic antidepressants

A
  1. Sedation
  2. Atropine-like (muscarinic blockade)- Blurred vision, sedation etc
  3. Postural hypotension
  4. Mania and convulsions
  5. Dysrhythmia and heart block
21
Q

What is another risk of tricyclic antidepressants

A
  1. Acute overdose:
  2. Prominent antimuscarinic
  3. Confusion, mania
  4. Cardiac arrhythmias
  5. Coma
  6. Respiratory depression
  7. Hypoxia
22
Q

What is problem with tricyclic antidepressants and drug interactions

A
  1. Alcohol
  2. Hypotensives
  3. NSAIDs
  4. MAOIs
  5. Rely on hepatic metabolism so compete with other drugs for inhibition
23
Q

What are Selective Serotonin Reuptake Inhibitors

A
  1. e.g. fluoxetine (Prozac), paroxetine citalopram
  2. Developed by Eli Lilly in 1980s on the concept that
  3. ‘biological’ components of depressive illness are sensitive to antidepressant effects on NA systems
  4. ‘emotional’ components of depressive illness are sensitive to antidepressant effects on 5-HT systems
  5. The most commonly prescribed class of antidepressants = 1st line
  6. Also used to treat anxiety disorders
24
Q

What are potential advantages of SSRIs over TCAs

A
  1. Better side-effect profile?
  2. Safer in overdose
  3. No evidence of greater efficacy
  4. No evidence of more rapid onset
  5. Newer drugs- Come with new patent and licensing exclusivity- more money
  6. Serotonin and noradrenaline uptake inhibitors (SNRIs) e.g. venlafaxine
    - Greater therapeutic efficacy?
    - Lower side effect profile?
    - More rapid onset
  7. Noradrenaline and dopamine uptake inhibitor e.g. bupropion
    - Depression with anxiety
    - Nicotine dependence, ADHD
25
Q

What are problems with the monoamine theory

A
  1. Immediate short-term pharmacological effects
  2. MAOIs increase 5-HT, NA by inhibiting metabolism
  3. TCAs increase 5-HT, NA by blocking reuptake
  4. SSRIs increase 5-HT by blocking reuptake
  5. Clinical effects always take 4-8 weeks to onset
  6. Suggests chronic adaptive changes in response to antidepressants rather than acute
26
Q

Describe 5-HT neurons modulation of activity

A
  1. 5HT neurones in raphe modulate activity of forebrain neurones via multiple receptors
  2. Raphe neurones have 5HT1A receptors to dampen and control firing
  3. Thought there is adaptation in 5HT 1a receptors and reduce amount of 5HT firing
  4. But become desensitised over time – why it takes weeks to see improvement in symptoms
27
Q

Which antidepressants can block monoamine receptors

A
  1. Mirtazapine – blocks alpha2 adrenoceptors/5HT2C receptors
    - Enhanced NA/5HT release
    - Faster acting, less side effects?
  2. Trazodone - blocks 5HT2A/2C but also 5HT reuptake
  3. Mianserin – blocks alpha1/2 adrenoceptors and a number of 5HT2A receptors,
  4. Newer antidepressants are ‘multimodal’ targeting both specific receptors and reuptake mechanisms e.g. vilazodone
28
Q

What are some limitations of anitdepressants

A
  1. Efficacy
    a) < 40% achieve full remission from symptoms
    b) Not very good – 20-30% better than placebo
    c) Robust effect in preventing relapse in recurrent MDD
  2. Tolerability
    a) side effect profile deters use e.g. emotional blunting/detachment with SSRIs
  3. Time to onset
    a) Typically 4-6 weeks to onset of therapeutic benefit
    b) discontinuation effects
  4. Safety
    a) older drugs are cardiotoxic, dangerous in overdose and can impair memory and pyschomotor performance
    b) risk of suicide
  5. Ketamine- promising new treatment
29
Q

How are bipolar disorders treated

A
  1. Lithium
  2. Anticonvulsants
  3. Atypical antipsychotics
30
Q

Describe use of lithium and side effects

A
  1. ~80% show stabilisation of mood
  2. Often given with antidepressants
  3. Used acutely - only reduce mania
  4. Used prophylactically - can reduce both mania and depression- long term
  5. Potentially serious side effect = lithium toxicity
  6. Needs plasma monitoring - effective at 0.5-1 mM but toxic >1.5 mM
31
Q

Describe use of anticonvulsants and side effects

A
  1. faster onset, safer, less side effects
  2. e.g. carbamazepine, valproate, lamotrigine
  3. control neuronal excitability
32
Q

Describe use of Atypical antipsychotics

and side effects

A
  1. faster onset, safer
  2. e.g. olanzapine, risperidone, quetiapine, aripiprazole
  3. Probably same as positive effects in psychosis
33
Q

Describe lithium toxicity

A
  1. Given by mouth and excreted by kidney
  2. Accumulates slowly
  3. Acute side effects
    a) polyuria and polydipsia (renal problems)
    b) weight gain
    c) aggravation/precipitation of skin disorders
    d) tremor, muscle twitching, dysarthria
    e) nausea, vomiting, appetite loss, diarrhoea
    f) sluggishness, languidness, drowsiness
    g) coma, hyper-reflexia, fasiculations
    h) choreiform and parkinsonian motor symptoms
    i) limb hyperextension, seizures and convulsions
  4. Chronic side effects
    a) thyroid goitre
    b) nephrotoxicity
    c) hair loss
34
Q

Describe action of lithium

A
  1. Monovalent cation that permeates voltage-gated sodium channels
  2. Not removed by Na/K ATPase
  3. Depolarization of excitable cells
  4. Inhibition of phosphatidyl inositol pathway
  5. Prevents agonist stimulated IP3 formation
    6 Inhibition of glycogen synthase kinase 3 (GSK3)
  6. Involved in apoptosis and amyloid formation
  7. Lithium beneficial in neurodegeneration?

A PA20023 (19 decks)

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