PCOL

• 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 (in psychology)


  Affective state, less specific, less intense and less likely to be provoked or instantiated by a particular stimulus or event
• Mood


  Temporary state of mind or feeling; how you feel at a present time
• Affective Disorders


  Mental illnesses characterized by pathological changes in MOOD
• Mania


  Also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together with lability of affect"; could cause brain impairment
• Elation


  Feeling of great joy
• Dysthymia


  People with this condition experience little to no joy in their lives
• According to a research in 2020: Bipolar - higher rate / more common in men, Unipolar - same with men and women
• Unipolar Disorders


  Depression - lower pole
• Bipolar Disorders


  Mania - upper pole; excessive happiness which may lead to brain degradation, Manic-depressive illness, Cycling Mood, Shifting between depression and mania, Appears earlier in life compare to unipolar
• Major Depressive Disorder (MDD)


  Characterized by DEPRESSED mood most of the time for at least 2 weeks or loss of interest or pleasure in most activities
• Symptoms of MDD


  • Chronic emptiness
  • Hopelessness
  • Fatigue
  • Unyielding sadness
  • Restlessness
  • No interest in hobbies
  • Feeling of guilt / low self-worth
  • Disturbed sleep
  • Low appetite
  • Low energy
  • Poor concentration
  • Suicidal thoughts
  • Easily irritable
• Medical conditions related to MDD


  • Chronic pain
  • Coronary artery disease (CAD)
  • Diabetes
  • Stroke
• Epidemiology of MDD


  Depression is two or three times as frequent in females than in males, It can occur at any age, but major incidence occurs at ages between 25-44 years old, Depressive disorders and suicide tend to cluster in families
• Etiology of MDD


  Alterations in brain monoamine neurotransmitters: norepinephrine, Serotonin and dopamine play a major role, Other factors include stressful events, medical illness
• Pathophysiology of MDD


  Neurotrophic hypothesis: Depression results from decreased neurotrophic support -> neuronal atrophy (alterations in the development) -> decreased hippocampal neurogenesis -> no growth or development -> Loss of glia, Antidepressants block or reverse the neuropathic factor deficit, Decreased / Loss of neurotrophic support -> Contributes to atrophic structural changes in the hippocampus, Hippocampus - Important in contextual memory and for regulation of hypothalamic-pituitary adrenal (HPA) axis; has a role in memory, mood emotions, Atrophy - arrested development; decreased size of the organ, Loss of neurotrophic support also affects the medial frontal cortex and anterior cingulate, Anterior cingulate – Involved in memory, learning and emotion, Medial Frontal Cortex – Plays a role in the integration of emotional stimuli and attention functions
• BDNF (Brain-derived neurotrophic factor)


  Plays an important role in neuronal survival and growth, A neurotransmitter modulator, Participates in the neuronal plasticity essential in learning and memory, Widely expressed in the CNS, Critical in regulation of neural plasticity, resilience and neurogenesis, Activates tyrosine kinase receptor B -> Influencing neuronal survival and growth effects, Damage in BDNF -> DECREASED HIPPOCAMPUS ACTIVITY -> ATROPHY -> DECREASED HIPPOCAMPAL FUNCTION -> DEPRESSIVE MOOD, Antidepressants enhance the BDNF, BDNF depletion - not sufficient to cause depressive behavior, it may result in a state of increased susceptibility easily triggered by stress, BDNF is important in activating the cAMP-response element binding protein (CREB) by stimulating the intracellular release of calcium ions, leading to the activation of CREB kinases. Once activated, neurons will attach to dendritic sprouts
• Monoamine Hypothesis


  Deficient in: Serotonin – compulsion, repetitive and stereotypical behavior, sleep, impulse, memory, sex, appetite, aggression, anxiety, irritability, Norepinephrine – for energy alertness, vigilance, concentration, attention, motivation , anxiety, irritability, Dopamine – attention, motivation, pleasure, reward-seeking, drive, sex, appetite, aggression, In the cortical and limbic system or corticolimbic system: Composed of prefrontal cortices, hippocampus and amygdala, integrates emotion with cognition and produces a behavioral output that is flexible based on the environmental circumstances, It also modulates pain, being implicated in pathophysiology of maladaptive pain, Altered number of receptors: 5HT1A and 5HT2C (serotonin 1a and 2c), Increase in 5HT1A, an autoreceptor, especially in the raphe nuclei, acts as a break to inhibit the 5HTsystem -> depression and resistance to antidepressants, 5HT2C-> may contribute in the depressive and anxiety symptoms in certain patients due to negative side effects; activation -> resistance to antidepressants, Alpha 2, Reduced amounts of metabolites in the CSF (Cerebrospinal fluid), Metabolite from the breakdown of serotonin: 5-hydroxyindoleacetic acid, Associated with violent and impulsive behavior including violent suicide attempts
• Neuroendocrine Factors Linked to Depression

  HPA (hypothalamic-pituitary-adrenal) abnormalities: In depression, this is upregulated with the downregulation of its negative feedback control, Increased Cortisol levels & Corticotropin Releasing Hormone = hypersecreted from the hypothalamus, Non-suppression of ACTH (Adrenocorticotropic hormone) release = induced release from pituitary, Thyroid dysregulation: When your thyroid doesn't produce enough hormones, the balance of chemical reactions in your body can be upset, Hypothyroidism-> associated with clinical depression, Sex steroids: Estrogen and Testosterone deficiency
• Therapy of Depression


  • Pharmacotherapy
  • Selective Serotonin Reuptake Inhibitors (SSRI)
  • Tricyclic antidepressants (TCA)
  • Monoamine oxidase inhibitors (MAOI)
  • Other and atypical antidepressant
  • Serotonin-2 Antagonist/Reuptake Inhibitors (SARI)
  • Serotonin and NE Reuptake Inhibitors (SNRI)
  • NE and Dopamine Reuptake Inhibitors (NDRI)
  • Noradrenaline Reuptake Inhibitors (NaRI)
  • Noradrenergic/Specific Serotonergic Antidepressants (NaSSA)
  • Non-pharmacological treatment: Psychotherapy (cognitive behavior therapy), Electroconvulsive therapy (ECT)
• Treatment Phases for Depression

  Acute = 6 weeks (Resolve symptoms), Continuation 6-9 months (Prevent relapse), Maintenance 3-5 years of lifelong (Prevent recurrence in high risk patients)
• Selective Serotonin Reuptake Inhibitors (SSRI)


  Block the reabsorption (reuptake) of serotonin into presynaptic neurons, Makes more serotonin available to improve transmission of messages between neurons, More modern and safe antidepressants
• Fluoxetine


  1st SSRI drug available in 1988, Principal mechanism of action: Selective inhibition of 5-HT (serotonin) reuptake (SERT) -> gradual complex changes in the density and/or sensitivity of both autoreceptors (5-HT1A) and postsynaptic receptors (important subtype 5-HT2A)
• Other indications of SSRI

  • Anxiety disorders: generalized anxiety, panic disorder, social anxiety disorder, obsessive compulsive disorder
  • Bulimia nervosa (a serious eating disorder, where you eat large amounts of food and then purge to get rid of extra calories), gambling, drug withdrawal
  • PMDD (Premenstrual Dysphoric disorder): a health problem that is similar to premenstrual syndrome (PMS) but is more serious. PMDD causes severe irritability, depression, or anxiety in the week or two before your period starts. Symptoms usually go away two to three days after your period starts
• Racemic Forms


  Not Optically Active, 50:50 mixture of two enantiomers; mirror images
• Racemic SSRI Forms


  • Fluoxetine
  • Paroxetine
  • Sertraline
  • Fluvoxamine
  • Citalopram
  • Escitalopram (S-enantiomer of Citalopram)
• Pharmacokinetics of SSRIs


  Good absorption after oral administration, Important biotransformation in the liver, Norfluoxetine (metabolite of Fluoxetine) with longest half life of all SSRIs, Single dose: UP TO 8.6 days, Repeated dose: 9.3 days, Long half-lives of elimination(s), fluoxetine (T1/2=50h) + active metabolite Norfluoxetine (T1/2 =240h), CYP450 inhibitors: CYP2D6 could inhibit = Fluoxetine, Paroxetine, CYP3A4 could inhibit = Fluvoxamine
• Drug Interactions of SSRIs

  Based on plasma protein binding and CYP blockade, Increased effect of co-administered TCA, beta-blockers, benzodiazepines etc.
• Adverse Effects of SSRIs

  • GIT: nausea, vomiting, abdominal cramps, diarrhea
  • Headache
  • Sexual dysfunctions (loss of libido, erectile dysfunction…)
  • Restlessness (akathisia: a movement disorder that makes it hard for you to stay still. It causes an urge to move that you can't control. fidgets)
  • Anxiety - an increase in anxiety or agitation during early treatment
  • Insomnia and fatigue
  • Serotonin syndrome upon intoxication or drug interaction
• Selective Serotonin - NE Reuptake Inhibitors (SNRI)


  Venlafaxine, Desvenlafaxine (Bicyclic), Duloxetine (Three ring structure), Milnacipran (for fibromyalgia: a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues)
• Indications of SNRIs


  • Major depression
  • Pain disorders (neuropathies, fibromyalgia)
  • GAD or Generalized anxiety disorder type
• Generalized anxiety disorder (GAD)


  Marked by excessive, exaggerated anxiety and worry about everyday life events for n
• Relative improvement to other antidepressants

  • Mostly mild
• Adverse effects of antidepressants

  • GIT: nausea, vomiting, abdominal cramps, diarrhea
  • Headache
  • Sexual dysfunctions: loss of libido, erectile dysfunction
  • Restlessness (akathisia)
  • Anxiety - an increase in anxiety or agitation during early treatment
  • Insomnia and fatigue
  • Serotonin syndrome upon intoxication or drug interaction
• Selective Serotonin - NE Reuptake Inhibitors (SNRI)


  Antidepressant class that inhibits the reuptake of both serotonin and norepinephrine
• SNRI drugs


  • Venlafaxine, Desvenlafaxine (Bicyclic)
  • Duloxetine (Three ring structure)
  • Milnacipran (for fibromyalgia)
• Indications for SNRI drugs

  • Major depression
  • Pain disorders (neuropathies, fibromyalgia)
  • GAD or Generalized anxiety disorder
  • Restlessness
  • Fatigue
  • Excessive anxiety
  • Increased muscle ache or soreness
  • Impaired concentration
  • Irritability
  • Difficulty sleeping
  • Stress urinary incontinence
  • Vasomotor symptoms of menopause
• Generalized anxiety disorder (GAD)


  Marked by excessive, exaggerated anxiety and worry about everyday life events for no obvious reason
• Stress urinary incontinence


  Unintentional loss of urine when physical movement or activity puts pressure on the bladder
• Vasomotor symptoms


  Symptoms that occur due to the constriction or dilation of blood vessels, including hot flashes, night sweats, heart palpitations, and changes in blood pressure