Drugs for Depression and Drugs for Psychotic Disorders

• Topics in Pharmacology of the Central Nervous System Part 2

  • Drugs for Depression
  • Drugs for Psychotic Disorders
• Bipolar Disorder


  Formerly called manic depression; characterized by extreme mood swings that include emotional highs (mania or hypomania) and lows (depression)
• Depression


  Feelings of sadness and hopelessness as well as inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, suicidal thoughts
• Mania


  Enthusiasm, rapid thought, and speech patterns, extreme self-confidence, and impaired judgement
• Pathophysiology of Major Depression involves potentiation, either directly or indirectly of the actions of NE and/or serotonin in the brain

  
• Biogenic amine theory


  Depression is due to the deficiency of monoamines such as NE and serotonin at certain key sites in the brain, and mania is caused by the overproduction of these neurotransmitters

  
• Neurotrophic Hypothesis

  Brain-derived neurotrophic factor (BDNF) is critical in the regulation of neural plasticity, resilience, and neurogenesis, and depression is associated with the loss of neurotrophic support
• Neuroendocrine Factors


  Depression is associated with a number of hormonal abnormalities such as elevated cortisol levels, non-suppression of ACTH release, chronically elevated levels of CRH, thyroid dysregulation, and sex steroid deficiency
• Anti-depressants have a delayed onset of therapeutic effects
• Selective Serotonin Re-uptake Inhibitors (SSRIs)


  Primary action is inhibition of the serotonin transporter (SERT), blocking the reuptake of serotonin and increasing its concentration in the synaptic cleft, with little blocking activity at other receptors
• SSRIs

  • Fluoxetine, Sertraline, Citalopram, Paroxetine, Fluvoxamine
• SSRIs


  • Highly lipophilic, used for obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, post-traumatic stress disorder, social anxiety disorder, bulimia nervosa
• Side effects of SSRIs

  • Nausea
  • Anxiety
  • Tremors
  • Weight loss
• SNRIs

  • Venlafaxine, Desvenlafaxine, Duloxetine, Levomilnacipran

  
• Uses of SNRIs


  • Major depression, treatment of pain disorders (neuropathies and fibromyalgia), treatment of generalized anxiety, stress urinary incontinence, and vasomotor symptoms of menopause
• Side effects of SNRIs

  • Nausea
  • Dry mouth
  • Dizziness
  • Excessive sweating
• Tricyclic Antidepressants (TCAs)


  Potent inhibitors of the neuronal reuptake of NE and serotonin, and also block serotonergic, α-adrenergic, histaminic, and muscarinic receptors

  
• TCAs

  • Amitriptyline, Clomipramine, Desipramine, Doxepin, Imipramine, Nortriptyline, Protriptyline, Trimipramine
• TCAs are substrates of the CYP2D6 system and their serum levels may be influenced by concurrent administration of drugs such as Fluoxetine
• Side effects of TCAs

  • Dry mouth
  • Urinary retention
  • Orthostatic hypotension
  • Sedation
• Monoamine Oxidase Inhibitors (MAOIs)


  • Inhibits MAO in the brain but also MAO in the liver and gut that catalyzes oxidative deamination of drugs and toxic substances such as tyramine.
  • forming stable complexes with the enzyme and causing irreversible inactivation, leading to increased stores of NE, serotonin and dopamine in neurons
• MAOIs

  • Phenelzine, Isocarboxazid, Tranylcypromine, Selegiline, and Moclobemide
• Uses of MAOIs

  • For depressed patients who are unresponsive or allergic to TCAs or who experience strong anxiety
• Side effects of MAOIs

  • Orthostatic hypotension
  • Blurred vision
  • Dryness of the mouth
  • Drowsiness
• Patients receiving MAOIs are unable to degrade tyramine from the diet, leading to release of large amounts of stored catecholamines and that leads to a hypertensive crisis

  
• 1. HT2 Receptor Modulators


  Blockade of the 5-HT2a receptor, with Nefazodone being a weak inhibitor of both SERT and NET but a potent 5-HT2a antagonist, and Trazodone being a weak but selective SERT inhibitor with its metabolite m-cpp being a potent 5-HT3 antagonist
• 1. HT2 Receptor Modulators

  • Trazodone, Nefazodone
• Side effects of 5-HT2 Receptor Modulators

  • Ataxia
  • Tremors
  • Confusion
  • Convulsion
• Lithium salts


  Used for treating manic-depressive patients and treatment of manic episodes
• Mood stabilizers for bipolar disorder

  • Lithium salts
  • Carbamazepine
  • Valproic acid
  • Lamotrigine
• Antipsychotics for psychotic disorders


  • Older (Chlorpromazine, Haloperidol)
  • Newer/Atypical antipsychotics (Risperidone, Olanzapine, Ziprasidone, Aripiprazole, Asenapine, Quetiapine)
• Schizophrenia


  Type of chronic psychosis characterized by delusions, hallucinations (often in form of voices), and thinking or speech disturbances, with a strong genetic component and probable biochemical abnormality in the mesolimbic or mesocortical dopaminergic pathways
• Serotonin Hypothesis of Schizophrenia

  1. HT2A blockade is a key factor in the mechanism of action of atypical antipsychotics, and stimulation of 5-HT2A can modulate the stability of a complex consisting of 5-HT2A and NMDA receptors, while stimulation of 5-HT2C inhibits cortical and limbic dopamine release
• Dopamine Hypothesis of Schizophrenia


  Excessive limbic dopaminergic activity plays a role in psychosis, while diminished cortical or hippocampal dopaminergic activity underlies the cognitive impairment and negative symptoms
• Glutamate Hypothesis of Schizophrenia


  Hypofunction of NMDA receptors located in GABAergic interneurons leads to decreased inhibitory influences and schizophrenia, with diminished GABAergic activity inducing disinhibition of downstream glutamatergic activity, leading to hyperstimulation of cortical neurons through non-NMDA receptors
• Antipsychotic Drugs

  Also known as Neuroleptics or Major Tranquilizers
• Diminished cortical or hippocampal dopaminergic activity


  Suggested to underlie the cognitive impairment and (-) symptoms of schizophrenia
• Dopamine hypothesis


  Decreased dopaminergic innervation in medial temporal cortex, dorsolateral prefrontal cortex, and hippocampus and decreased levels of DOPAC (metabolite of dopamine) has been reported in post-mortem studies
• Increased prefrontal D1 receptor levels


  Correlated with working memory impairments is seen in imaging studies
• Glutamate hypothesis


  • Glutamate is the major excitatory neurotransmitter in the brain
  • Hypofunction of NMDA receptors located in the GABAergic interneurons à decreased inhibitory influences on neuronal function à schizophrenia
  • Diminished GABAergic activity à induced disinhibition of downstream glutamatergic activity à hyperstimulation of cortical neurons through non-NMDA receptors