Affective Disorders (EL) (DONE) Flashcards
Affective disorders
Major depressive disorder- recurrent depressive episodes
Bipolar I disorder- manic episodes and depressive episodes
Bipolar II disorder- predominant depression, milder manic episodes
Attention deficit hyperactivity disorder (ADHD)
Anxiety
Cyclothymia
Persistent depressive disorder
Major depressive disorder
Recurrent episodes of depressed mood, social isolation with characteristic somatic symptoms
Lifetime prevalence of major depressive disorder 10-20%, gender difference, age of onset is highly variable
Genetics and environmental factors
Can be precipitated by stressful events
Second leading cause of disability worldwide
Three clinical subtypes: typical, atypical and psychotic
Depression
Emotional symptoms: low mood, apathy, motivational loss/decreased ability to experience pleasure, pessimistic or suicidal aspect
Biological/somatic symptoms: weight and appetite loss, sleep disturbance, loss of sex drive, motor retardation and muscle pain
Serotonin and noradrenaline
Serotonergic and noradrenergic signalling are intimately linked with mood regulation, motivation/reward, sleep, pain perception and numerous other physiological processes
Cross talk between the systems
Noradrenergic signalling
Vesicular monoamine transported is blocked by reserpine
Negative feedback through a2 autoreceptor agonism
Noradrenaline transporter facilitates the uptake of NA
Serotonergic signalling
Vesicular monoamine transporter is blocked by reserpine
Negative feedback through 5HT1b autoreceptor agonism
5HT transporter facilitates the uptake of 5HT
Monoamine theory of depression
Many clinically effective drugs have defines neurochemical actions on monoamines (5HT and NA) in the CNS
Imipramine and iproniazid elevate mood
Antihypertensive reserpine induced depression (VMAT blockade)
Everything pointed to monoaminergic involvement in depression pathogenesis
Drugs that affect monoaminergic signalling
TCAs: block NA and 5HT transporters, increase mood
MAOIs: inhibit MAO A and B, increase mood
Reserpine: VMAT inhibition, decrease mood
a-methlytyrosine: inhibits NA synthesis, decrease mood
Neural circuitry and depression
Brain regions involved: prefrontal and cingulate cortex, hippocampus, amygdala, striatum, thalamus
Neurons projecting from the locus coeruleus (NA) and raphe nuclei (5HT) innervate all these areas
Aetiology of depression
Monoamine theory of depression: a pathological deficiency in serotonergic and noradrenergic neurotransmission
As a result to treat depression we need to increase monoaminergic signalling
Drugs in depression
Tricyclic antidepressants e.g. amitriptyline
Selective serotonin reuptake inhibitors e.g. fluoxetine, citalopram
Serotonin and NA uptake inhibitors e.g. venlafaxine
Noradrenaline reuptake inhibitors e.g. atomoxetine, reboxetine
Atypical antidepressants e.g. mirtazapine, trazadone
Monoamine oxidase inhibitors- irreversible e.g. phenelzine, tranylcypromine; reversible e.g. moclobemide
Tricyclic antidepressants
Examples: amitriptyline, nortriptyline, dosulepin
5HT and NA transporter blockade
Side effects: short lasting sedation, confusion and incoordination in both normal and depressed patients, antimuscarinic effects, CV effects in overdose
Potentiation of the effects of alcohol
SSRIs
Fluoxetine, paroxetine, citalopram (escitalopram), sertraline
Inhibits 5HT transporter
Side effects: nausea, anorexia, insomnia and loss of sexual function
Interactions: NSAIDs, anticoagulants, triptans
SNRIs
Venlafaxine
Inhibits 5HT and NA transporter
Side effects: withdrawal effects
Interactions: NSAIDs, anticoagulants
MAOIs
Irreversible- tranylcypromine, reversible- moclobemide
Inhibits monoamine oxidase, non-selective (MAO-A and B)
Side effects: antimuscarinic effects, restlessness as a result of CNS excitation
Interactions: food/drink- cheese reactions
Cheese reaction
Occurs when amine that are generated during fermentation, like tyramine, are ingested and absorbed from the gut
Large rise in systemic tyramine indirectly results in a large release of catecholamines
Hypertensive crisis characterised by throbbing headache, tachycardia and cardiac arrhythmias
Atypical antidepressants
Mirtazapine
a2 autoreceptor antagonism, 5HT receptor antagonism
Side effects: sedation, weight gain, increased appetite, blood disorders, withdrawal
Interactions: alcohol
Mode of action of antidepressants
The time course of therapeutic effect is slow
Biochemical changes are fast
Are there slower changes relevant occurring?
Receptor down regulation/desensitisation
Changes in neural circuitry
Antidepressants
Work to increase monoaminergic signalling
This signalling change may bring about numerous cellular changes that result in amelioration of the symptoms of depression including:
Receptor desensitisation/downregulation
Receptor potentiation
Modification of BDNF expression
Meurogenesis
Neurogenesis and BDNF
The production of new neurones in the adult brain
Confined to subventricular zone and the subgranular zone of the dentate gyrus
Rodent HPC neurogenesis is reduced by stress and increased by antidepressant drugs
Controversial currently
Alternative therapies for depression
CBT
Electroconvulsive therapy
St Johns Wort
5HTP (5-hydroxytryptophan)
Ketamine
Ketamine is proving interesting as a fast acting antidepressant
Time course is hours rather than days
Stress causes depression by damaging nerve cells. Ketamine attacks the cell damage caused by glutamate- neurotrophic influence
Bipolar disorder
Depressive periods more common than periods of elevated mood
Can be mania or hypomania (mania with continuing functionality)
1% of population irrespective of nationality, ethnic origin or socioeconomic status
Aetiology of BP
Child of affected parent- 10 x risk of BP
High risk of suicide (20x general population), 1/3 to 1/2 attempt at some point
Often significant delay between disease onset and diagnosis
High heritability
No direct mendelian inheritance or genes of major effects but GWAS show susceptibility loci
Long term implications with cognitive deficits, CV disorders, diabetes and obesity common
