Depression

• Pathogenesis of depression

  Complex, not completely understood
• Factors that contribute to depression

  • Genetics
  • Difficulty in childhood
  • Chronic low self-esteem
• Monoamine deficiency hypothesis of depression

  Depression is caused by the functional insufficiency of monoamine neurotransmitters norepinephrine, serotonin or both
• Findings that support monoamine deficiency hypothesis

  • Induction of depression with reserpine
  • Induction of depression with inhibitors of tyrosine hydroxylase
  • Relief of depression with drugs that intensify monoamine mediated neurotransmission
• The monoamine deficiency hypothesis is a useful conceptual framework for understanding the antidepressant drugs, even though it is a little too simplistic
• Major treatment modalities for depression

  • Pharmacotherapy
  • Depression-specific psychotherapy
  • Somatic therapies (electroconvulsive therapy, transcranial magnetic stimulation)
• Mild to moderate depression


  Psychotherapy and pharmacologic therapy are equally effective
• Severe depression


  Requires both psychotherapy and pharmacologic therapy
• Electroconvulsive therapy


  Can be used when a rapid response is needed or when drugs and psychotherapy have not worked
• Drug classes for major depression

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs)
  • Tricyclic antidepressants (TCAs)
  • Monoamine oxidase inhibitors (MAOIs)
  • Atypical antidepressants
• All drug classes are equally effective, as are the individual drugs within each class
• Symptom resolution with antidepressants

  Initial responses develop after 1-3 weeks, maximal responses may not be seen for 12 weeks
• Assessing treatment failure


  A drug must be taken at least one month without success
• Considerations for drug selection

  • Tolerability
  • Safety
  • Drug interactions
  • Patient preference
  • Cost
• Drugs of first choice

  • SSRIs
  • SNRIs
  • Bupropion
  • Mirtazapine
• TCAs and MAOIs have more adverse effects
• Increased suicidal tendencies during antidepressant treatment


  Patients need to be observed closely for thoughts of suicide, worsening mood, change in behavior
• Assessing efficacy of initial drug

  Use for 4-8 weeks
• Dosage of antidepressants


  Start low and gradually increase
• Options if initial drug is not effective

  • Increase the dosage
  • Switch to another drug in the same class
  • Switch to another drug in a different class
  • Add a second drug, such as an atypical antidepressant
• Prescribing antidepressants


  Write prescriptions for the smallest number of doses consistent with good patient management, observe or monitor for suicide risk
• Follow up frequency


  Weekly for 4 weeks, then biweekly for 4 weeks, then monthly for 4 months, then periodically
• SSRIs


  Introduced in 1987, most commonly prescribed antidepressants, as effective as tricyclic antidepressants but with fewer side effects
• Therapeutic indications for fluoxetine

  • Depression
  • Bipolar disorder
  • Obsessive compulsive disorder
  • Panic disorder
  • Bulimia nervosa
  • Premenstrual dysphoric disorder
• Off-label uses for fluoxetine

  • Posttraumatic stress disorder
  • Social phobia
  • Alcoholism
  • ADHD
  • Tourette's syndrome
  • Obesity
• Mechanism of action of SSRIs

  Selectively block neuronal reuptake of serotonin, increasing its concentration in the synapse and causing increased activation of postsynaptic 5-HT receptors
• The blockade of 5-HT reuptake, by itself, cannot fully account for the therapeutic effects of SSRIs
• Onset of action of SSRIs

  Blockade of 5-HT reuptake occurs within hours, but depression relief takes several weeks
• Effect of fluoxetine on the CNS


  Produces excitation rather than sedation
• Adverse effects of fluoxetine

  • Sexual dysfunction (impotence, delayed/absent orgasm or ejaculation, decreased sexual interest)
  • Weight loss initially, then weight gain
  • Bruxism
  • Vivid dreams
  • Bleeding disorders
  • Increased perspiration
• Neonatal effects of fluoxetine use late in pregnancy

  Small risk for neonatal abstinence syndrome and persistent pulmonary HTN of the newborn, but low risk for birth defects
• Serotonin syndrome


  Possible adverse effect, usually starts 2-72 hours after treatment, can be life-threatening, resolves spontaneously when drug is discontinued
• The risk for serotonin syndrome is increased if the SSRI is given concurrent with MAOIs and other drugs
• Withdrawal syndrome


  Can occur if SSRIs are suddenly stopped, should be tapered
• MAOIs increase 5-HT availability and greatly increase the risk for serotonin syndrome

  MAOI should be stopped 2 weeks before starting an SSRI

  SSRI should be stopped 5 weeks before starting MAOI
• SSRI Interactions with other drugs

  SSRIs can elevate plasma levels of TCAs and lithium,

  increase risk of GI bleeding with antiplatelet/anticoagulant drugs,

  Highly protein bound - displace warfarin
• Other SSRIs available


  • Citalopram
  • Escitalopram
  • Fluvoxamine
  • Paroxetine
  • Sertraline
• Vilazodone


  Potential benefits include faster onset of action, greater efficacy, and better tolerability due to its SPARI (serotonin-reuptake inhibition with 5-HT1A partial agonism) properties
• Adverse effects of vilazodone

  • Nausea
  • Headache
  • Dry mouth
  • Dizziness
  • Bleeding
  • Hyponatremia
• Vilazodone has fewer sexual side effects compared to other antidepressants