affective disorders (depression: unipolar and bipolar)

Symptom of depression

• emotional components

• Biological components

Emotional components

• misery

• Apathy

• Pessimism

• Negative thoughts

• Loss of self esteem

• Feeling of guilt

• Feeling of inadequacy

• Indecisiveness

• Lack of motivation

• Anhedonia

• Loss of reward

• Suicidal thoughts

Biological components

• retardation of thought

• Slowness of action

• Loss of libido

• Sleep disturbance

• Loss of appetite

• Weight loss

• GI disturbance

Aetiology of mood disorders

• genetic factors

• Neurotransmitter dysfunction

• Psychosocial environment Factors

Brain areas involved in mood regulation

• frontal cortex

• hippocampus

• nucleus accumbens

• amygdala

• hypothalamus

• ventral tegmental area

• dorsal raphe nuclei

• locus coruleus

Functional and structural brain changes in depression

• prefrontal cortex

  • Reduced metabolism and volume.

• Amygdala

  • Increased activation to emotional stimuli

• Hippocampus

  • Reduced volume and impaired plasticity

Theories of depression

• monoamines hypothesis

• - neurotrophic hypothesis

• Neuro endocrine hypothesis

Monoamines: amino acid precursors

• catecholamines

  • Catechol ring (benzene 2 hydroxyl side groups)

  • Dopamine

  • Noradrenaline

  • Adrenaline

• Indolamine

  • Indole ring ( 6 membered benzene ring fused to 5 membered nitrogen containing)

  • Serotonin - 5HT

Catecholamines

Synthesis

• tyrosine

o Hydroxylation

• L-DOPA

o Decarboxylation

• dopamine

In noradrenergic neurones (only)

o Hydroxylation

• Noradrenaline

Inactivation

• Reuptake

o NET (norepinephrine transporter)

o DAT (dopamine transporter)

• Degradation

o monoamine oxidase (MAO)

o catechol-o-methyltransferase (COMT)

5 hydroxy tryptamine- 5HT

Synthesis

• tryptophan

  • Hydroxylation and decarboxylation

• 5HT

• Inactivation

• Reuptake

  • SERT

• Degradation

  • Monoamines oxidase

The monoamines theory of depression

Joseph schildkraut

• depression- a functional deficit of 5HT and/ or noradrenaline in the brain

• Mania- functional excess

• Originally from observation that:

  • Reserpine depletes NA/ 5HT vesicular stores- depression like behaviour

  • Isoniazid used for TB- elevated mood- blocked MAO

  • ECT for psychosis elevated mood- increase amine metabolites

  • Tryptophan increased 5HT elevated mood

  • Tryptophan hydroxylase blockade depresses mood

  • Inhibiting NA synthesis- depresses mood/ calms mania

  • Tricyclic antidepressant- developed for psychosis- elevated mood- blocked amine re- uptake

Conventional antidepressants

• MAO inhibitor

• TCAs

• SSRIs

• SNRIs

• Atypical

Monoamines oxidase inhibitors

• widely expressed peripherally and within neurones: inhibition increase monoamines avaliabilty

• Preferred substrates

• Elevated monoamines in cytoplasm not vesicles

• Spontaneous leakage increase receptor activation

• Cheese reaction

Cheese reaction

• MAO is also present in the gut and liver

• Tyramine metabolised by MAO

• MAO inhibition → tyramine enter the circulation

• Tyramine acts as an indirect sympathomimetic

• Enter noradrenergic nerve terminals

• Displace noradrenaline form storage vesicle

• Sudden, excessive noradrenaline release

• Acute hypertension

Classical tricyclic antidepressants TCAs

• first generation, still widely used, serious side effects

• Blocks re- uptake of amines by nerve terminals

  • 5HT= NA »DA

• Elevate released amine in synaptic cleft

• Competitive block with natural substrate

  • Non selective- imipramine, amitriptyline

  • NA selective- nortiptyline, desipramine

• Also blocks postsynaptic recpetor

  • Side effects: muscarinic ACh, histamine, 5HT

Clinical issues with TCAs

• major side effects

• Acute overdose

  • Drug interactions

Clinical issues with TCAs

• de methylated in vivo to active compounds

  • Imipramine to desipramine

  • Variation in metabolism rate between individual

  • Half lives ling

• Hepatic metabolism by CYP enzyme

  • May be inhibited by competing drugs

  • Also paroxetine and fluoxetine

  • Increase TCA toxicity

• Dangerous in overdose

  • Risk oof suicide

Selective serotonin reuptake inhibitors (SSRIs)

• 5HT> NA generally

• Based on concept that

  • Biological components of depression sensitive to effects on NA

  • Emotional components sensitive to effects on 5- HT

  • Normalise hyperactive amygdala response linked to fear and anxiety

  • Modulate serotongic signalling in the amygdala prefrontal cortex and hippocampus

• Fluoxetine first in class

  • Fluvoxamine, paroxetine, citalpram

SSRI considerations

• well absorbed

• Half lives

• 18-24h

• Fluoxetine longer

• Interactions may occur long after stopped

• Interact with CYP 2D6

• Some not used with TCAs

• General increased stimulation of 5HT receptor

• Risk of serotonin syndrome

  • When serotonin reuptake is inhibited and metabolism is reduced

    • Leading to excessive extracellular serotonin and receptor overactivation

SSRIs vs TCA

• better side effect profile

• Safer in overdose

• Non evidence of greater efficacy

• No evidence of more rapid onset

Serotonin and noradrenaline reuptake inhibitor (SNRIs)

• non selective for 5- HT and NA

  • Duloxetine

  • Venlafaxine

• Unwanted effects

  • Largely due to enhanced activation of adrenoreceptor

    • Headache

    • Insomnia

Atypical antidepressants

Mirtazapine

• a2 autoreceptor antagonist

• Autoreceptor feedback

• Increased NA release with antagonist drug

• Side effects

  • Sedation

Problem with the monoamines theory

• immediate short term pharmacological effects

  • MAOIs increase 5-HT, NA by inhibiting metabolism

  • TCAs increase 5-HT, NA by blocking reuptake

    • SSRIs increase 5-HT by blocking reuptake

Rapid acting antidepressant (RAADs)

• ketamine/ esketamine :NMDA receptor antagonist

• Rarely used in UK

• Rapid and sustained antidepressant effects

  • Produced rapid antidepressant effects

• Effects occur too quickly to be explained by monoamines adaptation alone

• Suggest involvement of other mechanisms

  • Glutametergic signalling and rapid changes in synaptic plasticity

    • NMDA receptor are considered by key regulators of synaptic plasticity

Drugs in depression

• tricyclic antidepressant (TCAs) e.g amitriptyline

• Selective serotonin reuptake inhibitors e.g fluoxetine

• Serotonin and NA uptake inhibitors e.g venlafaxine

• Atypical antidepressant e.g mirtazapine

• Monoamines. Oxidase inhibitors (MAOIs)

How do we treat depression

• limited to severe, drug refractory depression

• General anaesthesia

• Muscle relaxant or block

• Electrodes bilateral or unilateral

• Induction of brief tonic clonic seizure

• Short lasting, need repetition

• Confusion and memory deficits are issues

Bipolar disorders

• Bipolar I

  • Severe mood swings from mania to depression

• Bipolar II

  • Milder mood swings mania alternating with severe depression

• Cyclothymia- brief hypomania alternating with brief hypomania alternating with brief milder depressive symptoms

  • Not as long lasting as seen in full mania or depressive episiodes

• Mania

  • Mood

• Thought

• Activity

• Sleep

Biological basis

• less well understood

• Some susceptibility genes shared with schizophrenia

• Increased monoamines neurotransmission activity

  • Especially 5HT and dopamine

• Reduced ACh and GABA neurotransmission activity

• May affect:

  • Prefrontal cortex, visual association context