Affective Disorders (EL) (DONE)

Question 1

Affective disorders

Answer 1

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

Question 2

Major depressive disorder

Answer 2

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

Question 3

Depression

Answer 3

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

Question 4

Serotonin and noradrenaline

Answer 4

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

Question 5

Noradrenergic signalling

Answer 5

Vesicular monoamine transported is blocked by reserpine
Negative feedback through a2 autoreceptor agonism
Noradrenaline transporter facilitates the uptake of NA

Question 6

Serotonergic signalling

Answer 6

Vesicular monoamine transporter is blocked by reserpine
Negative feedback through 5HT1b autoreceptor agonism
5HT transporter facilitates the uptake of 5HT

Question 7

Monoamine theory of depression

Answer 7

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

Question 8

Drugs that affect monoaminergic signalling

Answer 8

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

Question 9

Neural circuitry and depression

Answer 9

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

Question 10

Aetiology of depression

Answer 10

Monoamine theory of depression: a pathological deficiency in serotonergic and noradrenergic neurotransmission
As a result to treat depression we need to increase monoaminergic signalling

Question 11

Drugs in depression

Answer 11

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

Question 12

Tricyclic antidepressants

Answer 12

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

Question 13

SSRIs

Answer 13

Fluoxetine, paroxetine, citalopram (escitalopram), sertraline
Inhibits 5HT transporter
Side effects: nausea, anorexia, insomnia and loss of sexual function
Interactions: NSAIDs, anticoagulants, triptans

Question 14

SNRIs

Answer 14

Venlafaxine
Inhibits 5HT and NA transporter
Side effects: withdrawal effects
Interactions: NSAIDs, anticoagulants

Question 15

MAOIs

Answer 15

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

Question 16

Cheese reaction

Answer 16

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

Question 17

Atypical antidepressants

Answer 17

Mirtazapine
a2 autoreceptor antagonism, 5HT receptor antagonism
Side effects: sedation, weight gain, increased appetite, blood disorders, withdrawal
Interactions: alcohol

Question 18

Mode of action of antidepressants

Answer 18

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

Question 19

Antidepressants

Answer 19

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

Question 20

Neurogenesis and BDNF

Answer 20

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

Question 21

Alternative therapies for depression

Answer 21

CBT
Electroconvulsive therapy
St Johns Wort
5HTP (5-hydroxytryptophan)

Question 22

Ketamine

Answer 22

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

Question 23

Bipolar disorder

Answer 23

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

Question 24

Aetiology of BP

Answer 24

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

Question 25

Pathophysiology of BP

Answer 25

Evidence for involvement of monoaminergic pathways but no single dysfunction identified
Synaptic and neurpplasticity implicated
Common with depression, BDNF and spine density implicated
Common genetic pathways implicate aberrant calcium signalling through voltage gated calcium channels
Pathology supports altered calcium signalling, alleviated by lithium

Question 26

Treatment options )BP)

Answer 26

Antipsychotics, mood stabilisers (lamotrigine and lithium)
Antidepressants- evidence for efficacy unclear
Limited specific drug trials to clarify best drugs/combination treatments
Strong evidence for olanzapine plus fluoxetine
Lamotrigine requires 6 week titration period (not for mania)

Question 27

Lithium in bipolar disorder

Answer 27

Lithium has been used as a mood stabiliser for more than 50 years
Complex not fully understood mechanism of action
One potential mechanism is that lithium inhibits recycling of inositol substrates leading to decreased IP3 and DAG
Narrow therapeutic index/therapeutic drug monitoring- lithium toxicity
Only drug shown to reduce suicide risk