Affective disorders: Neurobiology and treatment Flashcards
Describe the neurobiology of major depression
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
Give the aetiology of depression
Multifactorial
Incompletely understood
Interactions of genetic factors, childhood adversities, past hx of mood disorders, psychological predisposition (neuroticism)
Often precipitated by stressful life events
What do all traditional antidepressants affect?
5HT/NA systems
Describe antidepressants in 1950
Monoamine oxidase inhibitors (MAOIs) - Anti-TBC drug having euphorigenic effect
Tricyclics (TCAs) - anti-histaminic having antidepressant effect
List some antidepressants
Monoamine oxidase inhibitors (MAOIs) Tricyclics (TCAs) Trazodone Fluoxetine (Prozac) Bupropion Venlafaxine Mirtazapine Duloxetine Agomelatine Vortioxetine
What do all traditional antidepressants cause
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
Describe monoamine oxidase inhibitors
Nonselectively inhibit enzymes involved in the breakdown of monoamines, including serotonin, dopamine, and norepinephrine
Name some monoamine oxidase inhibitors
Phenelzine, Tranylcypromine
Name some tricyclic antidepressants
Amytryptiline, Clomipramine
Describe the action of tricyclic antidepressants
Nonselectively inhibit the reuptake of monoamines, including serotonin, dopamine, and norepinephrine
List some second generation antidepressants
SSRI: Selective serotonin reuptake inhibitors
SNRI: Serotonin-noradrenaline reuptake inhibitors
alpha2 and 5-HT2Cantagonist [modulate serotonin and NA release]
Dopamine-noradrenaline reuptake inhibitor
Name some SSRI: Selective serotonin reuptake inhibitors
Sertraline, Citalopram, Escitalopram, Fluoxetine
Name some SNRI: Serotonin-noradrenaline reuptake inhibitors
Venlafaxine, Duloxetine
Name some alpha2 and 5-HT2Cantagonist [modulate serotonin and NA release]
Mirtazapine
Name some Dopamine-noradrenaline reuptake inhibitor
Bupropion (not approved as antidepressant in UK)
Describe SSRIs
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
What are the side effects of SSRIs?
gastro-intestinal symptoms (nausea, diarrhea)
headache, Irritability, Anxiety
reduction of libido and sexual dysfunction
What are the side effects of monoamine oxidases inhibitors?
Dry mouth, GI side effects, headache, drowsiness, insomnia, dizziness, food interactions (hypertension crises)
What are the side effects of tricyclic antidepressants?
Constipation, orthostatic hypotension, dry mouth, drowsiness, cardiac toxicity in overdose
Give the side effects of Venlafexine
nausea,vertigo, headache, insomnia
Give the side effects of Mirtazapine
drowsiness, sedation, hypotension, increased appetite and weight gain
Describe HPA dysfunction in mood disorders
Lack of dexamethasone suppression
Glucocorticoid receptor alterations
Depression in Cushing’s syndrome
Describe the relationship between depression and inflammation
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)
What happens to the size of the hippocampus in depression?
Decreases
Describe the neural systems involved in depression
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
List some factors which contribute to the cause of bipolar disorder
Catecholamines Oxidative stress Neutrophins Inflammation Stress hormones, glucocorticoids
What is the purpose of short term treatment?
To reduce the severity and shorten the duration of the acute episode and achieve remission of symptoms
What is the purpose of long term treatment?
prevention of new episodes and to achieve adequate inter-episode control of residual or chronic mood symptoms
List some categories of drug treatments of bipolar
Antipsychotics
Lithium
Anticonvulsants
Antidepressants
List the receptors targeted in antipsychotics
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)
What do antipsychotics cause?
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
What is lithium and what is it used to treat?
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
Describe the mechanism of action of lithium
Multiple neurotransmitters (including DA)
Cellular signalling
Neurotrophic factors
Describe the adverse effects of lithium
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
List some anticonvulsants
Valproate
Lamotrigine
Carbamazepine
Describe valproate
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
When should valproate not be used?
not be used for women of child bearing potential because of its unacceptable risk to the foetus of teratogenesis and impaired intellectual development
Describe Lamotrigine
actions via GABA, Glutamate and sodium channel blockade
Mostly effective in prevention of depressive relapses
Ineffective as anti-manic agent
Describe carbamazepine
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
Describe the treatment of depressive episodes
Antipsychotics (Quetiapine, lurasidone)
Fluoxetine/Olanzapine combinations
Antidepressants to be co-prescribed with an anti-manic drug
Consider Lamotrigine (usually with antimanic drug)
Describe the treatment of acute manic episodes
Dopamine antagonists (haloperidol, olanzapine, risperidone and quetiapine)
Valproate
Discontinue any antidepressant treatment
Describe the long term treatment of bipolar disorder and the prevention of new episodes
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
State the adverse effects of long term preventative treatment
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)
