Antidepressant Drugs and the Psychopharmacology of Depression Flashcards
(33 cards)
Explain the evidence for the monoamine theory of depression.
- Overall reduced activity of central adrenergic and serotonergic systems
- Reserpine depletes NA and 5-HT and induces depression
- Main antidepressant drugs increase monoamine concentrations in the brain
Explain the evidence against the monoamine theory of depression.
- Difficult to show deficits of 5-HT and NA in brain
- Most antidepressants take several weeks for effect but increase in amines is acute
- Some antidepressants weak/no effect on 5-HT and NA - e.g. trazodone
- Cocaine blocks amine uptake but has no antidepressant effect
- Decrease in 5-HT in bipolar linked to aggression, not depression
Explain the neuroendocrine theory of depression.
- NAergic and serotonergic neurons input to hypothalamus
- Hypothalamus releases CRH
- CRH stimulates release of ACTH from anterior pituitary
- Increased [ACTH] in blood stimulates cortisol release from adrenal cortex
- CRH - behavioural effects mimic depression
- Increased plasma [cortisol] in depressed patients
- [CRH] in CSF of depressed patients
How does the hippocampus provide evidence for the neuroendocrine theory of depression?
- Decreased hippocampal feedback in depression
- Decreased glucocorticoid (cortisol) receptors in hippocampus
- Tactile stimulation just after birth activates 5-HT pathways to hippocampus
- 5-HT triggers long-lasting increase in expression of glucocorticoid receptor gene - increased GC receptors in hippocampus
- SSRIs - increased GC receptors in hippocampus
Describe the evidence behind the neuroplasticity and neurogenesis theory of depression.
- Evidence of neuronal loss and decreased neuronal activity in hippocampus and prefrontal cortex (decision making centres)
- Antidepressants and electroconvulsive therapy (ECT) promote neurogenesis in these regions
- 5-HT promotes neurogenesis during development (BDNF)
- Increase in glutamate in cortex of depressed people - NMDA antagonists potential for treatment - e.g. ketamine
Outline the 2 main psychological treatments for depression.
- Cognitive Behavioural Therapy (CBT) - aims to recognise and change negative cognitive processes and thus improve mood and counterproductive behaviours
- Interpersonal Therapy - assumes that depression is multi-factorial but that interpersonal difficulties play a central role
Describe and explain the main effects of MAOIs.
- Increased [5-HT] > [NA] > [DA}
- Increased NA - increased euphoria, motor activity
- Downregulation of α2, 5HT1A, β1, β2, 5HT2A, 5HT3
- MAOIs non-specific - reduce metabolism of opioid analgesics and alcohol
What is the MAOI “cheese effect”?
- MAO in gut is inhibited
- Dietary amines e.g. tyramine get into circulation
- Cheese, yoghurt, meat, wine, yeast products all contain high concentraitons of tyramine
- Tyramine displaces NA from vesicles - acts as an indirect sympathomimetic
- NA accumulation - hypertension, Incre headache, intracranial haemorrhage
Describe the main side effects of MAOIs. When are MAOIs used as a treatment?
- Postural hypotension (peripheral sympathomimetic/accumulation of DA displace NA in vesicles); dizziness
- Excessive central stimulation can lead to tremors, excitement & insomnia; in overdose - convulsions
- Appetite and weight gain (5-HT receptor downregulation)
- Antimuscarinic effects (dry mouth, constipation, blurred vision, difficulty in micturition)
Consequently MAOIs only used in severe depression when other ADs do not work.
What are RIMAs? Give an example and explain why they may be preferred to MAOIs.
- RIMA = reversible MAOI (reversible inhibitor MA) - e.g. moclobemide
- Accumulation of NA displaces RIMA, allowing degradation of excess NA
- RIMAs safer than MAOIs and selective RIMAs (moclobemide) better tolerated - no major side effects
Describe the main effects and characteristics of TCAs.
- NA and 5-HT reuptake inhibitors
- Initially increase [NA] and [5-HT] in synpatic cleft
- Chronic treatment - downregulation of β1, 5-HT2
- Downregulation of α2, 5-HT1A/1D (autoR)
- TCAs take a long time to produce effects
Desipramine and imipramine are structurally what type of amines?
3rd degree/tertiary amines
Describe the interactions of TCAs with cholinergic, histamine and adrenergic receptors.
- Anti-muscarinic (M1) - constipation, blurred vision, dry mouth, drowsiness
- Antihistamine - H1 antagonist - weight gain and sedation
- α adrenergic antagonist in medullary vasomotor centre - decreased BP, postural hypotension, tachycardia, dizziness
Under what circumstances are TCAs not used?
- Suicide risk (overdose can induce heart attack)
- In elderly or dementia patients - confusion
- Patients with heart disease - TCAs block K+ channels, may cause dysrythmia
Describe the drug interactions associated with TCAs.
- Antipsychotics, steroids - inhibit TCA metabolism
- TCAs potentiate effects of alcohol and anaesthetics - respiratory depression
Why is it easy to overdose on TCAs?
TCAs have a narrow therapeutic window
NICE recommends the use of which antidepressant class due to it having less side effects?
SSRIs
Describe the main effects and characteristics of SSRIs.
- 5-HT reuptake inhibitor
- Chronic action - increased [5-HT] causes downregulation of 5-HT1A/1D autoreceptors, disinhibition of 5-HT neurons > positive feedback > perpetuates 5-HT release
- Increased [5-HT] downregulates postsynaptic 5-HT receptors - “normalising” effect
Describe the therapeutic and side effects of 5-HT2A and 5-HT3 receptor activation
- 5-HT2A - antidepressant, anti-OCD, insomnia, sexual dysfunction
- 5-HT3 - nausea, GI distress, diarrhoea, headache
Why are SSRIs thought to be safer and better-tolerated than other antidepressant classes?
- Lack of anticholinergic effect and no cardiotoxicity - better compliance and recommended for long-term use
- Broader therapeutic profile
What drug class is thought to be more effective than SSRIs for severe depression?
TCAs
Name 3 disadvantages of SSRIs
- Shorter t1/2 - risk of withdrawal effects
- Increased risk of suicidal behaviour under 18
- 5-HT3 - associated with increased violence
Alongside depression, SSRIs are also used for what 3 other conditions?
- Anxiety
- GAD
- OCD
Why are SSRIs not used in combination with TCAs and MAOIs?
- SSRIs inhibit TCA metabolism
- Excessive 5-HT release > serotonin syndrome
- Serotonin sydnrome - tremor, seizures, hyperthermia, cardiovascular collapse
