LESSON 9

• Mood


  Pervasive and sustained emotion that in extreme, markedly affects the person's perception of the world and the ability to adequately function in the society
• Mood Disorders

  • Unipolar
  • Bipolar

  
• Unipolar


  • Depression (Major depressive disorder/clinical depression)
  • Mania (Abnormally elevated arousal energy level)
  • Hypomania (Milder form of mania. Mood state or energy level that is elevated above normal, but not so extreme as to cause impairment)
  • Dysthymia (Persistent depressive disorder)

  
• Bipolar


  Moods which cycle between mania and depression

  
• Cyclothymia


  Persistent unstable moods that cycle between elation and dysthymia
• Depression


  • Also known as: MDD (Major Depressive Disorder)
  • Characterized by: Depressed mood most of the time for at least 2 weeks, loss of interest or pleasure in most activities, Disturbances in sleep and appetite deficits in cognition and energy, Thoughts of guilt, worthlessness, and suicide (recurrent thoughts of death)
  • Occurrence: Two or three times as frequent in females than in males, Can occur at any age but major incidence at 25-44 years old, Occur with other serious medical conditions, Tend to cluster in families
• Psychiatrist


  Medical doctors (MD) that prescribe medication to their patient, Address both mental and psychological aspects of mental disorders (rooted in biology or neurochemistry)
• Psychologist


  Degree in Psychology that provide wide array of talk therapy, Address conditions rooted in emotion or behavior
• Pathophysiology of Depression


  • Neurotrophic Hypothesis: Depression is associated with the loss of neurotrophic support from nerve growth factors such as BDNF
  • MAO Hypothesis: Depression is related to a deficiency in the amount or function of cortical and limbic 5-HT, NE and dopamine
  • Abnormalities in Hormone: Increase in cortisol level, Thyroid desregulation, Sex steroids (estrogen and testosterone deficiency)
• SSRI (Selective Serotonin Re-uptake Inhibitors)


  The most common antidepressant in clinical use, More modern and safe antidepressants

  
• SSRI Pharmacokinetics


  Highly lipophilic, Good absorption after oral administration, Important biotransformation in the liver, Norfluoxetine (metabolite of Fluoxetine) has longest half life (T1/2= 240hr), Enzyme inhibitor: Fluoxetine, Paroxetine= CYP2D6; fluvoxamine = CYP3A4

  
• SSRI Mechanism of Action


  Selective inhibition of 5-HT (serotonin) reuptake (SERT), Gradual complex changes in the density and/or sensitivity

  
• Other indications of SSRI


  • Anxiety disorders (Generalized anxiety, panic disorder, social anxiety disorder, obsessive-compulsive disorder)
  • Bulimia nervosa (Fluoxetine)
  • Drug withdrawal
  • PMDD (Premenstrual Dysphoric disorder) (Fluoxetine and Sertraline)
• SSRI Adverse Effects


  • Gastrointestinal effects (nausea, gastrointestinal upset, diarrhea)
  • Sexual effects (loss of libido, delayed orgasm, or diminished arousal)
  • Increase in headaches and insomnia or hypersomnia
  • Discontinuation syndrome (dizziness, paresthesias)
  • Serotonin syndrome (drug interaction or upon intoxication)
• Serotonin Syndrome


  A condition of too much serotonin in the body, A potentially life-threatening drug reaction that may result from therapeutic medication use, self-poisoning, or interactions between drugs

  
• SNRI (Serotonin and NE Reuptake Inhibitors)


  Two classes of antidepressants that act as combined serotonin and norepinephrine reuptake inhibitors, Differ from TCAs in lacking potent antihistamine, α-adrenergic blocking, and anticholinergic effects

  
• SNRI Examples


  • Venlafaxine
  • Desvenlafaxine
  • Duloxetine
  • Milnacipran
• SNRI Indications


  • Major depression
  • Pain disorders (neuropathies, fibromyalgia)
  • GAD/ general anxiety
  • Stress urinary incontinence
  • Vasomotor symptoms of menopause
• SNRI Mechanism of Action


  Binds and inhibits both the SERT and NET
• SNRI Adverse Effects


  • Nausea, vertigo (both frequent and may improve), hypertension, manic reactions
  • Duloxetine - with hepatic toxicity in patients with a history of liver damage
• TCA (Tricyclic Antidepressants)


  Chemical structure: three-ring nucleus (lipophilic nature), Originally developed as antipsychotics (1949), but were found to have no effect in this indication, Clinical use and efficacy is relatively similar within the group, The more significant difference is in their adverse effects

  
• TCA Mechanism of Action


  Blockade of re-uptake of noradrenaline (NA) and serotonin (5-HT) by competition for binding site of the carrier protein (NET and SERT), Other actions: Blockade of H1-receptor, α-receptors, M-receptors

  
• TCA Pharmacokinetics


  Administered orally, Rapid absorption, extensive first pass effect ⇒ low and inconsistent BAV, Strong binding to plasma proteins (90-95% bound), Wide distribution in tissues (high lipophilicity) = large distribution volumes, Biotransformation in the liver (CYP450, N-demethylation and tricyclic ring hydroxylation), Most metabolites are active

  
• TCA Adverse Effects


  • Anticholinergic (atropine-like) due to M-blockade
  • Postural (orthostatic) hypotension + reflex tachycardia due to α-blockade of adrenergic transmission
  • Blockade of sodium channel in the myocardium- cardiac arrhythmias
  • Sedation, drowsiness, difficulty in concentration - H1-blockade
  • Sexual dysfunction (loss of libido, impaired erection)
  • Weight gain- H1 blockade
  • Seizure
• MAO Inhibitors (Monoamine Oxidase Inhibitors)


  MAO enzymes: MAO-A and MAO-B, MAO-A generally metabolizes tyramine, norepinephrine (NE), serotonin (5-HT), and dopamine (DA), MAO-B mainly metabolizes dopamine (DA), Inhibition of intracellular enzyme MAO in CNS neurons (= decrease in degradation of catecholamines and serotonin)
• MAO Inhibitor Types


  • Hydrazines (Irreversible non-selective (MAOA and MAOB) inhibitors, long lasting inhibition)
  • Non-hydrazines (Reversible Inhibitors of MAO-A (RIMA))
• Hydrazine MAO Inhibitors


  • Phenelzine (Nardil)
  • Tranylcypromine (Parnate)
  • Isocarboxacid

  
• Non-hydrazine MAO Inhibitors


  • Moclobemide (Aurorix)
• MAO Inhibitor Adverse Effects


  • Orthostatic hypotension
  • Weight gain/ increased appetite
  • Anorgasmia
  • Discontinuation syndrome (delirium-like presentation, Psychosis, Excitement, Confusion)
  • CNS stimulation – tremor, excitement, insomnia, convulsions in overdose
  • Rare severe hepatotoxicity (hydrazine MAOI)
• MAO Inhibitor Drug and Food Interactions


  • MAOIs + Tyramine rich food (cheese, wine, fermented foods) = Hypertensive Crisis
  • MAOIs + SSRI/ TCA/ opioids e.g. pethidine = Serotonin syndrome
  • MAOIs + BZD/ Alcohol/ Antihistamine = Enzyme inhibition, prolong and profound the effect, increase sedation
• 5HT2A Antagonists


  Used in depression with significant anxiety and sleep disturbances, Antagonist also on H1 and α1 and α2- receptors, Inhibits 5HT reuptake (central) and blocks 5HT2 receptor (peripheral)
• 5HT2A Antagonist Examples


  • Trazodone (Desyrel)
  • Nefazodone (Serzone)

  
• 5HT2A Antagonist Adverse Effects


  • Sedation
  • Gastrointestinal disturbances
  • Priapism
• MAOIs + SSRI/ TCA/ opioids e.g. pethidine


  Serotonin syndrome: confusion, agitation and excitation, tremor, fever, sweating, nausea, diarrhea, sleep disruption
• MAOIs + BZD/ Alcohol/ Antihistamine


  Enzyme inhibition, prolong and profound the effect, increase sedation
• 5HT2A ANTAGONISTS


  Serotonin 2a receptor antagonists

  
• 5HT2A ANTAGONISTS


  • Used in depression with significant anxiety and sleep disturbances
  • Antagonist also on H1 and α1 and α2- receptors
• Mechanism of action of 5HT2A ANTAGONISTS


  1. It inhibits 5HT reuptake (central)

  2. It block 5HT2 receptor (peripheral)

  
• 5HT2A ANTAGONISTS


  • Trazodone (Desyrel)
  • Nefazodone (Serzone)
• Nefazodone received an FDA black box warning in 2001 implicating it in hepatotoxicity, including lethal cases of hepatic failure