Affective disorders: Neurobiology and treatment

Question 1

Describe the neurobiology of major depression

Answer 1

Adverse childhood experience, current stress, genetic factors- decreased 5HT and NA function
Current stress and genetic factors - HPA Axis function - cortisol - Decreased 5HT and NA function

Question 2

Give the aetiology of depression

Answer 2

Multifactorial
Incompletely understood
Interactions of genetic factors, childhood adversities, past hx of mood disorders, psychological predisposition (neuroticism)
Often precipitated by stressful life events

Question 3

What do all traditional antidepressants affect?

Answer 3

5HT/NA systems

Question 4

Describe antidepressants in 1950

Answer 4

Monoamine oxidase inhibitors (MAOIs) - Anti-TBC drug having euphorigenic effect

Tricyclics (TCAs) - anti-histaminic having antidepressant effect

Question 5

List some antidepressants

Answer 5

Monoamine oxidase inhibitors (MAOIs)
Tricyclics (TCAs)	
Trazodone 
Fluoxetine (Prozac)
Bupropion 
Venlafaxine 
Mirtazapine
Duloxetine
Agomelatine
Vortioxetine

Question 6

What do all traditional antidepressants cause

Answer 6

5-HT concentrations (acute tryptohan depletion) studies
Decreased reduced 5-HT Transporter in post-mortem suicide studies
Reduced 5-HT Transporter in DepressionPET/SPECT studies

Question 7

Describe monoamine oxidase inhibitors

Answer 7

Nonselectively inhibit enzymes involved in the breakdown of monoamines, including serotonin, dopamine, and norepinephrine

Question 8

Name some monoamine oxidase inhibitors

Answer 8

Phenelzine, Tranylcypromine

Question 9

Name some tricyclic antidepressants

Answer 9

Amytryptiline, Clomipramine

Question 10

Describe the action of tricyclic antidepressants

Answer 10

Nonselectively inhibit the reuptake of monoamines, including serotonin, dopamine, and norepinephrine

Question 11

List some second generation antidepressants

Answer 11

SSRI: Selective serotonin reuptake inhibitors
SNRI: Serotonin-noradrenaline reuptake inhibitors
alpha2 and 5-HT2Cantagonist [modulate serotonin and NA release]
Dopamine-noradrenaline reuptake inhibitor

Question 12

Name some SSRI: Selective serotonin reuptake inhibitors

Answer 12

Sertraline, Citalopram, Escitalopram, Fluoxetine

Question 13

Name some SNRI: Serotonin-noradrenaline reuptake inhibitors

Answer 13

Venlafaxine, Duloxetine

Question 14

Name some alpha2 and 5-HT2Cantagonist [modulate serotonin and NA release]

Answer 14

Mirtazapine

Question 15

Name some Dopamine-noradrenaline reuptake inhibitor

Answer 15

Bupropion (not approved as antidepressant in UK)

Question 16

Describe SSRIs

Answer 16

Efficacy equal to tryciclics in outpatients
Large spectrum of action (OCD, PTSD, Panic, GAD, social anxiety)
Low toxicity and safe in overdose

The initial treatment phase is the most delicate, due to prevalence of side effects over benefits – slow titration

Question 17

What are the side effects of SSRIs?

Answer 17

gastro-intestinal symptoms (nausea, diarrhea)
headache, Irritability, Anxiety
reduction of libido and sexual dysfunction

Question 18

What are the side effects of monoamine oxidases inhibitors?

Answer 18

Dry mouth, GI side effects, headache, drowsiness, insomnia, dizziness, food interactions (hypertension crises)

Question 19

What are the side effects of tricyclic antidepressants?

Answer 19

Constipation, orthostatic hypotension, dry mouth, drowsiness, cardiac toxicity in overdose

Question 20

Give the side effects of Venlafexine

Answer 20

nausea,vertigo, headache, insomnia

Question 21

Give the side effects of Mirtazapine

Answer 21

drowsiness, sedation, hypotension, increased appetite and weight gain

Question 22

Describe HPA dysfunction in mood disorders

Answer 22

Lack of dexamethasone suppression
Glucocorticoid receptor alterations
Depression in Cushing’s syndrome

Question 23

Describe the relationship between depression and inflammation

Answer 23

Raised plasma cytokine levels and inflammatory markers
High comorbidity between chronic inflammation and depression
Administration of cytokines promotes depressive symptoms
Microglial activation in brain of depressed patients (PET studies)

Question 24

What happens to the size of the hippocampus in depression?

Answer 24

Decreases

Question 25

Describe the neural systems involved in depression

Answer 25

``` Increased activity (Amy; VST, PFC) to negative emotional stimuli (fearful faces) Decreased activity (VST) to positive emotional stimuli, and during receipt and anticipation of reward ``` bias of attention towards negative emotional stimuli, and away from positive emotional and reward- related stimuli Neural systems that are important to understand major depressive disorder include those that support emotion processing, reward seeking, and regulate emotion, all of which are dysfunctional in the disorder. These systems include subcortical systems involved in emotion and reward processing

Question 26

List some factors which contribute to the cause of bipolar disorder

Answer 26

``` Catecholamines Oxidative stress Neutrophins Inflammation Stress hormones, glucocorticoids ```

Question 27

What is the purpose of short term treatment?

Answer 27

To reduce the severity and shorten the duration of the acute episode and achieve remission of symptoms

Question 28

What is the purpose of long term treatment?

Answer 28

prevention of new episodes and to achieve adequate inter-episode control of residual or chronic mood symptoms

Question 29

List some categories of drug treatments of bipolar

Answer 29

Antipsychotics Lithium Anticonvulsants Antidepressants

Question 30

List the receptors targeted in antipsychotics

Answer 30

D2/D3 antagonist 1st generation: Haloperidol D2/D3 antagonists (also targeting 5-HT) (2nd generation: Olanzapine, Risperidone, Quetiapine, Lurasidone, Asenapine, Amisulpride, Clozapine) DA partial agonist (Aripiprazole)

Question 31

What do antipsychotics cause?

Answer 31

Rapid anti-manic effect Often used long-term to maintain same treatment effective in acute episode Long-term adverse effects on weight, glucose regulation and lipids [except for Aripiprazole, Amisulpride, and Lurasidone] Full D2 antagonism (Haloperidol) may cause EPSEs

Question 32

What is lithium and what is it used to treat?

Answer 32

Element, present in food and drinking water Treatment of bipolar disorder Anti-suicidal effects Possible efficacy on impulsive and violent behaviours Strongest evidence for prevention of relapses of any polarity

Question 33

Describe the mechanism of action of lithium

Answer 33

Multiple neurotransmitters (including DA) Cellular signalling Neurotrophic factors

Question 34

Describe the adverse effects of lithium

Answer 34

Narrow therapeutic index blood tests every 3 months for the 1st year Adverse long-term effects on Kidney function with excessive levels Risk of Lithium toxicity

Question 35

List some anticonvulsants

Answer 35

Valproate Lamotrigine Carbamazepine

Question 36

Describe valproate

Answer 36

Actions via GABA, intracellular signalling, sodium channel blockade, epigenetic modulation, etc. Anti-manic and effective in prevention of mania Useful in combination, but potential pharmacokinetic interactions

Question 37

When should valproate not be used?

Answer 37

not be used for women of child bearing potential because of its unacceptable risk to the foetus of teratogenesis and impaired intellectual development

Question 38

Describe Lamotrigine

Answer 38

actions via GABA, Glutamate and sodium channel blockade Mostly effective in prevention of depressive relapses Ineffective as anti-manic agent

Question 39

Describe carbamazepine

Answer 39

less effective in maintenance treatment than lithium but may be used as monotherapy if lithium ineffective especially in patients who do not show the classical pattern of episodic euphoric mania almost exclusively effective against manic relapse pharmacokinetic interactions

Question 40

Describe the treatment of depressive episodes

Answer 40

Antipsychotics (Quetiapine, lurasidone) Fluoxetine/Olanzapine combinations Antidepressants to be co-prescribed with an anti-manic drug Consider Lamotrigine (usually with antimanic drug)

Question 41

Describe the treatment of acute manic episodes

Answer 41

Dopamine antagonists (haloperidol, olanzapine, risperidone and quetiapine) Valproate Discontinue any antidepressant treatment

Question 42

Describe the long term treatment of bipolar disorder and the prevention of new episodes

Answer 42

Consider long-term treatment following a single severe manic episode Lithium as initial monotherapy (target serum level range: 0.6-0.8 mmol/l) Alternatives (if Lithium ineffective, poorly tolerated or unlikely adherence to treatment): Valproate Dopamine antagonists/partial agonists Carbamazepine

Question 43

State the adverse effects of long term preventative treatment

Answer 43

``` Weight gain (most medications, particularly Olanzapine and Quetiapine) Metabolic syndrome (Olanzapine, Quetiapine, Risperidone) Hyperprolactinemia (Dopamine antagonists) Tardive dyskinesia (much reduced risk with newer agents) ``` Liver damage (e.g. Valproate) Kidney and Thyroid dysfunction (poorly regulated Lithium)