Depressive Disorders Lecture Review

Epidemiology of Major Depressive Disorder (MDD)

• Major Depressive Disorder is recognized as one of the most common psychiatric disorders.

• Lifetime Prevalence: The lifetime prevalence is estimated at $15-20\%$.

• Average Onset: Typically occurs during late adolescence to early adulthood.

• Gender Distribution: Women are affected twice as often as men, reflecting a $2:1$ ratio.

• Course: The disorder is often recurrent.

• Comorbidities: MDD is frequently comorbid with anxiety disorders and substance use disorders.

Depression vs Normal Sadness

MDD Prognosis and Recurrence

• MDD is characterized by an extremely high rate of recurrence.

• Early Recurrence: Following a single episode, the rate of recurrence over the next $2$ months is >40\%.

• Long-term Recurrence: Within $5$ years, the rate of recurrence is >75\%.

• Risk Factors: Incomplete remission of the initial episode is strongly associated with a higher risk of subsequent recurrence.

Etiology and Neurobiology of Depressive Disorders

• Key Neurotransmitters:

  • Serotonin ($5-HT$): Influences mood, anxiety, sleep, appetite, and pain perception. Pathways originate in the raphe nuclei and project throughout the brain to regulate emotions.

  • Norepinephrine ($NE$): Influences alertness, energy, focus, and the stress response. Pathways originate in the locus coeruleus and project to the cortex to influence attention and motivation.

  • Dopamine ($DA$): Supports motivation, reward, pleasure, movement, and learning. Pathways originate in the ventral tegmental area ($VTA$) and substantia nigra, projecting to the limbic system and frontal cortex.

• Additional Biological Factors:

  • Genetics.

  • Neuroinflammation.

  • Chronic stress.

  • Neuroplasticity changes.

  • Hypothalamic-Pituitary-Adrenal ($HPA$) axis dysfunction.

• The Monoamine Hypothesis:

  • Theory: This theory suggests that a deficiency in monoamines (serotonin, norepinephrine, and dopamine) contributes directly to depression.

  • Mechanism: When monoamines are deficient, monoamine receptors upregulate.

  • Evidence: While direct evidence is lacking and the pathophysiology is recognized as a complex heterogeneous mix of inflammatory, excitotoxic, and endocrine factors, all available antidepressants act on the monoamine system.

Depression = "Bio + Psycho + Social"

Bio: Genes, neurotransmitters, cortisol
Psycho: Negative thoughts, helplessness
Social: Stress, trauma, isolation

Monoamine Hypothesis: ↓ Serotonin + ↓ Norepinephrine + ↓ Dopamine → Depressive symptoms.

Screening and Diagnosis of MDD

• Diagnostic Tools: Clinical interviews, discussions with friends/family, laboratory work, review of prior treatment records, and the Patient Health Questionnaire ($PHQ-9$).

• Screening Guidelines for Adults ($\ge 18$ years): Annual screening is recommended using either the $PHQ-2$ or $PHQ-9$.

• Screening Guidelines for Adolescents: Annual screening starting at age $12$ using the $PHQ-A$ (modified for ages $11-17$).

• The PHQ-9 Questionnaire: Assesses symptoms over the past $2$ weeks:

  1. Little interest or pleasure in doing things.

  2. Feeling down, depressed, or hopeless.

  3. Trouble falling/staying asleep or sleeping too much.

  4. Feeling tired or having little energy.

  5. Poor appetite or overeating.

  6. Feeling bad about oneself or failing the family.

  7. Trouble concentrating.

  8. Psychomotor retardation or agitation (moving slowly or being fidgety).

  9. Suicidal ideation or thoughts of self-harm.

• PHQ-9 Scoring and Proposed Treatment:

  • $0-4$: None-minimal severity; no treatment required.

  • $5-9$: Mild severity; watchful waiting and repeat $PHQ-9$ at follow-up.

  • $10-14$: Moderate severity; treatment plan considering counseling, follow-up, and/or pharmacotherapy.

  • $15-19$: Moderately severe severity; active treatment with pharmacotherapy and/or psychotherapy.

  • $20-27$: Severe severity; immediate initiation of pharmacotherapy and expedited referral to a mental health specialist if impairment is severe.

Mimics of Depressive Disorders

• Anemia

• Sleep Apnea

• Vitamin Deficiency: Low levels of certain vitamins, such as B12 and D, can contribute to depressive symptoms and affect energy levels.

• Chronic Illness

DSM 5 Criteria for Major Depression Disorder vs. Major Depressive Episode

• Major Depressive Disorder: A persistent low mood lasting at least two weeks with symptoms affecting daily functioning, including loss of interest or pleasure, significant weight change, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or excessive guilt, difficulty concentrating, and recurrent thoughts of death. Patient have a history of at least 1 major depressive episode and there is no history of mania or hypomania.

• Major Depressive Episode: A shorter duration diagnosis characterized by the same symptom criteria but does not necessarily recur, and can occur in the context of other mood disorders. It can occur in bipolar disorder, schizoaffective disorder and substance abuse depression.

MDD Clinical Specifiers

• Specifiers are descriptive modifiers added to a diagnosis to describe the clinical presentation (e.g., Major Depressive Disorder, recurrent, severe, with anxious distress).

• List of Specifiers:

  • With anxious distress.

  • With mixed features.

  • With melancholic features.

  • With atypical features.

  • With mood-congruent psychotic features.

  • With mood-incongruent psychotic features.

  • With catatonia.

  • With peripartum onset.

  • With seasonal pattern.

• Peripartum Onset Specifier:

  • Affects $3-6\%$ of women during pregnancy or in the weeks/months following delivery.

  • $50\%$ of postpartum episodes actually begin prior to delivery.

  • Can be applied up until $1$ year postpartum.

• Catatonia Specifier:

  • Characterized by mutism (no interaction), negativism (resistance to movement), posturing, waxy flexibility, and echolalia (repeating words).

  • Treatment: Lorazepam ($Ativan$).

Depressive Disorder Specifiers and Special Populations

DSM-5-TR allows clinicians to add specifiers to Major Depressive Disorder (MDD) to describe important symptom patterns, prognosis, and treatment considerations.

Remission and Severity Definitions

• In Partial Remission: A period lasting less than $2$ months without significant symptoms following an episode.

• In Full Remission: During the past $2$ months, no significant signs or symptoms of the disturbance were present ($2+$ months).

• Severity Levels:

  • Mild: Symptoms are present but manageable, with only minor impairment in social/occupational functioning.

  • Moderate: Symptom count and intensity fall between mild and severe.

  • Severe: Numerous, unmanageable symptoms that markedly interfere with functioning.

Persistent Depressive Disorder (Dysthymia)

• Diagnostic Criteria:

  • Depressed mood for most of the day, for more days than not, for at least $2$ years (at least $1$ year for children/adolescents).

  • During the $2$-year period, the individual has never been without symptoms for more than $2$ months at a time.

  • Criteria for MDD may be present continuously for the $2$ years.

  • No history of manic or hypomanic episodes; criteria for cyclothymic disorder have never been met.

• Comparison of MDD vs. PDD:

  • MDD: Episodic, lasts $\ge 2$ weeks, often more severe, may fully remit.

  • PDD: Chronic, lasts $\ge 2$ years, often milder, persistent symptoms.

MDD vs. Persistent Depressive Disorder vs. Premenstrual Dysphoric Disorder

Suicide Risk Assessment and Safety Planning

• Columbia Severity Suicide Rating Scale ($C-SSRS$):

  • Differentiates between active and passive suicidal ideation ($SI$).

  • Questions: Inquire about wishing to be dead, thoughts of killing oneself, methods, intention, and specific plans.

  • Evaluation: Assess onset, frequency, duration, prior attempts, and access to lethal means (guns, knives, medications).

• Safety Plan Components:

  • Warning signs.

  • Coping strategies.

  • Support contacts.

  • Crisis numbers (e.g., $988$ Suicide & Crisis Lifeline).

  • Restricting lethal means.

Treatment Principles for MDD

• Goals: Sustained remission (defined as PHQ-9 < 5) and improved social/occupational functioning.

• Response: Defined as a reduction in symptom score of $\ge 50\%$ that remains above the remission threshold.

• Settings: Use the least restrictive setting: Outpatient < Intensive Outpatient < Inpatient.

• Treatment by Severity:

  • Mild: Psychotherapy first.

  • Moderate-Severe: Combination of medication and psychotherapy.

  • Severe/Suicidal/Psychotic: Urgent psychiatric intervention.

• Prescribing Guidelines:

  • Choice is based on side effect profiles and comorbidities, as most antidepressants have similar efficacy.

  • "Start low and go slow."

  • Meds take $4-6$ weeks for full effect, though mild changes may be seen at $2$ weeks.

  • Black Box Warning: All antidepressants carry a warning for increased suicidal ideation in patients under $25$ years old.

Serotonin Syndrome

• Definition: Life-threatening excess of serotonergic activity.

• Classic Triad:

  1. Mental status changes (agitation, confusion).

  2. Autonomic instability (hypertension, tachycardia, hyperthermia, diaphoresis).

  3. Neuromuscular hyperactivity (tremor, clonus, hyperreflexia, muscle rigidity).

• SHIVERS Mnemonic: Shivering, Hyperreflexia/myoclonus, Increased temperature, Vital sign instability, Encephalopathy, Restlessness, Sweating.

• Treatment: Stop all serotonergic agents, supportive care (IV fluids), sedation with benzodiazepines. Severe cases require cooling and Cyproheptadine.

TCA Overdose

TCA overdose is a medical emergency because it can rapidly cause life-threatening cardiac arrhythmias, seizures, and hypotension.

• Tri-Cyclic Antidepressants (TCAs) can cause significant toxicity, presenting with anticholinergic symptoms, CNS depression, and cardiovascular complications.

• Management includes ensuring a clear airway, providing IV fluids, administering activated charcoal if within 1 hour of ingestion, and cardiac monitoring.

• Classic Clinical Presentation

  • "3 C's of TCA Toxicity"

Discontinuation Syndrome

• Advise patients to NEVER abruptly stop medications

• Typically will taper off medications over several weeks or cross taper onto new medication

• FINISH Acronym (Flu Like Symptoms, Insomnia, Nausea, Imbalance, Sensory Disturbances, and Hyperarousal)

• Supportive Care: Providing supportive management through hydration, rest, and, if necessary, adjunctive medications to alleviate symptoms. | | Prevention | Gradual tapering of medications instead of stopping abruptly, particularly for those known to cause discontinuation syndrome.

Postpartum Depression Specific Treatments

• Brexanolone ($Zulresso$): Neuroactive steroid ($GABA-A$ modulator). Administered as a $60$-hour continuous IV infusion. Requires continuous pulse-ox monitoring due to risk of sudden loss of consciousness.

• Zuranolone ($Zurzuvae$): Oral version of brexanolone. Dose $50\,mg$ daily for $14$ days. Works quickly (approx. $3$ days). Cost is approximately $16,000$ for the course.

Non-Medication Treatments

• CBT: Just as effective as antidepressants; best results when combined with medication.

• Light Box Therapy: Used for Seasonal Affective Disorder. Intensity should be $10,000\,lux$. Reduces melatonin production.

• Electroconvulsive Therapy (ECT): Most effective treatment for depression. Induces a generalized seizure. Requires maintenance to prevent relapse.

• Transcranial Magnetic Stimulation (TMS): Modulates cortical regions (left dorsolateral prefrontal cortex). Used for depression unresponsive to $2$ prior antidepressants.

Anti-Depressants & Special Patient Populations

• Geriatrics

  Category	Key Points
  Prevalence of Depression in the Elderly	Depression is common among geriatric populations, often exacerbated by comorbid medical conditions, loss of loved ones, and social isolation.
  Pharmacokinetics Changes	Aging affects drug metabolism, leading to altered pharmacokinetics. Drugs may have prolonged half-lives, increasing the risk for adverse effects.
  Commonly Used Antidepressants	SSRIs (Selective Serotonin Reuptake Inhibitors): Generally preferred due to their favorable side effect profile, e.g., sertraline, escitalopram. Do NOT use Paroxetine! Avoid using Bupropion if they have a history of seizures.
  	SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Can be effective but may cause increased blood pressure, e.g., venlafaxine.
  	Avoiding Tricyclic Antidepressants (TCAs): Due to anticholinergic effects which can lead to confusion, urinary retention, and cardiotoxicity.
  Potential Side Effects	Increased risk of falls due to dizziness or sedation.
  	Monitor for hyponatremia (especially in SSRI use).
  	Watch for serotonin syndrome, especially when used with other serotonergic drugs.
  Drug Interactions	Geriatric patients frequently take multiple medications, increasing the risk for drug-drug interactions. For instance, SSRIs can interact with anticoagulants, increasing bleeding risk.
  Dosing Considerations	Start at lower doses and titrate slowly due to sensitivity in this population. “Start slow, go low”
  	Regular monitoring of renal

• Pregnancy

  Category	Key Points
  Prevalence of Depression	Depression can occur during pregnancy and may affect about 10-20% of pregnant women.
  Risks of Untreated Depression	Untreated depression during pregnancy is associated with complications such as preterm birth, low birth weight, and increased risk of postpartum depression.
  Commonly Used Antidepressants	SSRIs (e.g., fluoxetine, sertraline) and SNRIs (e.g., venlafaxine) are often prescribed during pregnancy due to their safer profile compared to other medications. DO NOT prescribe Paroxetine and avoid SNRIs!
  Potential Risks	Some studies suggest a small increased risk of congenital malformations, particularly with paroxetine. Long-term exposure has been associated with neonatal adaptation syndrome.
  Monitoring	Close monitoring of maternal mental health and fetal development is essential, including risks and benefits of continuing or discontinuing medication during pregnancy.
  Postpartum Considerations	Women with a history of depression are at higher risk for postpartum depression, requiring potential continuation of antidepressant therapy during the breastfeeding period.