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Antidepressants (Unipolar Depression treatment (Inhibitors of 5HT and NA…

- - - - Monoamine reuptake -TCAs
      - pronounced effects of re-elevating mood
    - - activate psychomotor drive
      - Monoamine metabolism - MAOIs
  - - - MAO-A selective
        
        MAO-A is associated with mitochondria, which
        are present in high concentrations in nerve terminals
        
        inhibition of MAO-A
        
        Increase in cytoplasmic 5HT and NA
        
        Efflux of NT via reuptake transporter (not exocytosis)
        
        increase of external 5HT and NA
        
        antidepressant effects used especially for "Agitated Depression" (depression with anxiety)
        
        irriversilble
        
        Clorgyline
        
        reversible
        
        Moclobemide
        
        Brofaromine
        
        Pirlindole
        
        Toloxatone
        
        problems
        
        MAO-A present also in intestinal Mucosa and Liver
        
        metabolise dietary amines to prevent
        passage into systemic circulation
        
        inhibition causes increase in systemic/plasma tyramine, which leads to the displacement of endogenous NA from sympathetic nerve terminals and causing:
        
        vasculature A1-mediated hypertension
        
        heart B1-mediated tachycardia
        
        cheese reaction
        
        potentiation of sympathomimetics
        
        overdose -> fatal respiratory depression, especially with alcohol or barbiturates
        
        postural hypotension
        
        increased motor activity and excitability
        
        MAO - monoamine oxidase - degrades monoamines
      - MAOB
        
        increase conc of B-phenylethylamine and Benzylamine
        
        not antidepressants
      - non-selective
        
        increase conc of DA and Tyramine
        
        Iproniazid
        
        Isocarboxazid
        
        Phenyelzine
        
        Tranylcypromine
  - - - SERT - tranporter (reuptake) of 5HT
      - NET - transporter (reuptake) of NA
    - - tertiary amines - more selective for SERT
        
        Imipramine
        
        Clomipramine
        
        Amitriptyline
      - secondary amines - more selective for NET
        
        Desipramine
      - problems
        
        take 2-3 weeks to show the effects
        
        lack of selectivity
        
        A1-adrenoceptor antagonism
        
        Postural Hypotension
        
        H1R antagoism
        
        Sedation
        
        mAChR antagonism
        -dry mouth, blurred vision, constipatione etc
        
        Acute cardiotoxicity
        
        overdose and drug interactions (e.g. alcohol) are life-threatening
    - - Zimelidine
      - Fluoxetine (prozac)
      - Citalopram
        
        most selective for SERT
      - Paroxetine
        
        most potent for SERT
      - Vortioxetine
      - Problems
        
        GI effects - lots of 5HTRs in GI tracts
        
        Rash/tremor/urticaria
        
        loss of libido
        
        no/less A1/H1/mAChR antagonism or acute cardiotoxicity
        +safer in overdose in comparison to TCAs
    - - selective for NET
      - Maprotiline
    - - selective for SERT and NET but not for DAT
      - Venlafaxine
      - low therapeutic dose SERT>NET
      - high therapeutic doses SERT=NET
  - - - Presynaptic A2-adrenoceptor
        
        Gi/o signalling
        
        Inhibition of NA and 5HT release
      - Presynaptic 5HT1A receptor
        
        Gi/o signalling
        
        Inhibition of NA and 5HT release
  - - - phosphodiesterase inhibitory
      - Type IV PDE -> increased cAMP/PKA -> increased synthesis and release of NA (numerous side effects)
  - - - NA reuptake inhibition
      - A2-adrenoceptor antagonist (decreased presynaptic feedback, causing inhibition of NA and 5HT release
    - - A2-adrenoceptor antagonist (decreased NA release)
      - presynaptic 5HT receptors inverse agonist/antagonist
        (decreased 5HT release)
    - - Serotonin antagonist and reuptake inhibitor (SARI)
- - - - disorder of mood rather than thought or cognition
    - - about 5-10% succeed
  - - - Depressed mood, misery, pessimism
      - Anhedonia
      - Low self-esteem, guilt, inadequacy
      - poor concentration
      - Indecisiveness and lack of motivation
      - feeling hopeless and helpless
      - suicidal thoughts
      - Hypochondria
    - - retardation of thought and action (cognitive deficits)
      - Fatigue
      - Loss of apetite (weight loss)
      - sleep disturbance
      - aches and pains
      - loss of libido
    - - Psychomotor agitation or retardation
      - Self-neglect
  - - - reactive, non familial
        
        associated with stressful life events/anxiety/agitation
        
        (75%)
      - Endogenous, familial pattern
        
        distinct symptomology related to stress
        
        (25%)
    - - depression alternating with Mania over periods of weeks
      - Mania component - excessive exuberance, enthusiasm, self-confidence, coupled with impulsivity and occasionally irritability/impatience/aggression and grandiose delusion
      - Early adult presence, strong hereditary tendency