Depression

• Mood disorders


  Psychological - abnormal elevation or lowering of mood
• Types of mood disorders

  • Bipolar disorders
  • Unipolar disorders
  • Bipolar I
  • Bipolar II
  • Cyclothymia
  • Major depression
  • Dysthymic disorder
• Mood disorders are a leading cause of psychiatric disability and suicide
• Mood/Affective disorders


  • Mood - conscious state of mind or predominant emotion
  • Mood disorders - psychological - abnormal elevation or lowering of mood
• Mood disorders can occur with anxiety and psychosis
• Depression


  An abnormal mental condition characterised by feelings of severe despondency and dejection, with feelings of inadequacy and guilt, often accompanied by lack of energy and disturbance of appetite and sleep. It can be progressive and unremitting
• Sadness


  A normal human emotion usually triggered by a difficult, hurtful, challenging, or disappointing event, experience, or situation. When our emotional hurt fades, and we've adjusted to our loss or disappointment, our sadness remits
• Types of depression


  • Reactive depression
  • Endogenous depression
• Reactive depression is non-familial, associated with stressful events, and temporary. Endogenous depression is familial, not related to external stressors, and more likely episodic, recurrent and chronic
• Symptoms of depression


  • Emotional components: misery, apathy, pessimism, negative thoughts, loss of self-esteem, feelings of guilt, feelings 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 disturbances
• Factors contributing to mood disorders


  • Biological vulnerability: genetic factors, gender
  • Biological dysfunction in mood circuits, connectivity, transmitter function, regulation, control
  • Depressive episode: psychosocial stressors e.g. trauma, illness, bereavement
  • Neurotransmitter dysfunction: monoamines, neuroendocrine, neurogenesis, glutamate
  • Psychosocial/environmental factors: life events e.g. marriage breakdown, loss of job, co-morbidity e.g. chronic pain, substance abuse
• Brain areas involved in mood regulation

  • Frontal cortex (prefrontal and cingulate) - cognitive function, attention
  • Hippocampus - cognitive function, memory
  • Nucleus Accumbens - reward and aversion
  • Amygdala - responses to emotional stimuli
  • Hypothalamus - sleep, appetite, energy, sex
  • Ventral Tegmental Area - Dopamine projections to other areas
  • Dorsal Raphe nuclei - 5HT (serotonin) input to other areas
  • Locus Coeruleus - noradrenaline input to other areas
• Functional and structural brain changes in depression include reduced frontal cortex metabolism and volume, and increased amygdala activation
• Theories of depression


  • Monoamine hypothesis
  • Neurotrophic hypothesis
  • Neuroendocrine hypothesis
• Catecholamines


  Dopamine, noradrenaline, adrenaline
• Catecholamine synthesis


  Tyrosine -> Hydroxylation -> L-DOPA -> Decarboxylation -> Dopamine

  In noradrenergic neurones: Hydroxylation -> Noradrenaline
• Catecholamine inactivation


  Reuptake by NET (norepinephrine transporter) and DAT (dopamine transporter)

  Degradation by monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT)
• 1. HT synthesis


  Tryptophan -> Hydroxylation -> 5-HT
• 1. HT inactivation


  Reuptake by SERT (serotonin transporter)

  Degradation by monoamine oxidase (MAO)
• Monoamine theory of depression


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

  Mania - functional excess
• Monoamine theory evidence


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

  Isoniazid blocks MAO - elevated mood

  ECT for psychosis - increased amine metabolites

  Tryptophan increased 5-HT - elevated mood

  Tryptophan hydroxylase blockade - depressed mood

  Inhibiting NA synthesis - depressed mood/calmed mania

  Tricyclic antidepressants blocked amine re-uptake - elevated mood
• Antidepressant drug classes


  • Monoamine oxidase inhibitors

  Tricyclic antidepressants

  Selective serotonin reuptake inhibitors (SSRIs)

  Serotonin-norepinephrine reuptake inhibitors (SNRIs)

  Atypical antidepressants
• Monoamine oxidase inhibitors


  Elevate monoamines in cytoplasm, not vesicles, leading to spontaneous leakage and increased receptor activation

  Cheese reaction - tyramine (in cheese etc) normally metabolized by MAO, in high quantities can cause severe hypertension
• Tricyclic antidepressants


  Block reuptake of amines by nerve terminals, elevating released amines in synaptic cleft

  Non-selective - imipramine, amitriptyline, clomipramine

  NA selective - nortriptyline, desipramine

  Also block postsynaptic receptors
• Side effects of tricyclic antidepressants


  • Sedation

  Atropine-like (muscarinic blockade)

  Postural hypotension

  Mania and convulsions

  Dysrhythmia and heart block

  Acute overdose - confusion, mania, cardiac arrhythmias, coma, respiratory depression, hypoxia
• Tricyclic antidepressants have long half-lives, are metabolized by CYP enzymes, and can have dangerous interactions and toxicity in overdose
• Side effects of antidepressants


  • Block re-uptake of amines by nerve terminals
  • Elevate released amines in synaptic cleft
  • Competitive block with natural substrate
  • Non-selective - imipramine, amitriptyline, clomipramine
  • NA selective - nortriptyline, desipramine
  • Also block postsynaptic receptors
• Side effects of antidepressants


  • Muscarinic ACh
  • Histamine
  • 5HT
• Imipramine


  Demethylated in vivo to active compound desipramine
• Tricyclic antidepressants (TCAs)


  • Major side effects: Sedation
  • Atropine-like (muscarinic blockade)
  • Postural hypotension
  • Mania and convulsions
  • Dysrhythmia and heart block
• Tricyclic antidepressants (TCAs) in acute overdose


  • Prominent antimuscarinic effects: Confusion, mania
  • Cardiac arrhythmias
  • Coma
  • Respiratory depression
  • Hypoxia
• Tricyclic antidepressants (TCAs)


  • Long half-lives
  • Hepatic metabolism by CYP enzymes
  • May be inhibited by competing drugs like antipsychotics, paroxetine and fluoxetine
  • Increase TCA toxicity
• Lofepramine


  Safest tricyclic antidepressant in overdose
• Dosulepin


  Tricyclic antidepressant with 2 week supply considered dangerous in overdose
• Affective disorders are a spectrum including unipolar (reactive vs endogenous) and bipolar disorders
• Monoamines involved in depression

  • 5HT
  • Dopamine
  • NA
• Monoamine theory of depression


  • Treatments: MAO inhibitors - prevent breakdown of monoamines
  • TCAs - 5HT=NA>>DA (5-HT and NA transporter blockade)
• Selective Serotonin Reuptake Inhibitors (SSRIs)


  5HT>NA, based on concept that 'biological' components of depression sensitive to effects on NA, 'emotional' components sensitive to effects on 5-HT
• Selective Serotonin Reuptake Inhibitors (SSRIs)


  • Well absorbed
  • Half lives 18-24h, fluoxetine longer (24-96h)
  • Interact with CYP2D6
  • Some not used with TCAs to avoid increased TCA toxicity
• Selective Serotonin Reuptake Inhibitors (SSRIs)


  • Unwanted effects: General increased stimulation of 5HT receptors
  • With MAOIs - risk of Serotonin Syndrome (can be fatal)
  • Withdrawal effects: Anxiety/agitation