Depression

Epidemiology

• Prevalence:

  • Approximately 17% of the US population reports a major depressive episode in their lifetime.

• Gender Discrepancy:

  • Depression occurs in women more often than men, with a ratio of 2:1.

• Age of Onset:

  • The average age of onset for depression is in the mid-20s.

  • Over 50% of patients experience their first episode by age 40.

• Duration:

  • If left untreated, episodes can last between 6 months to 2 years.

  • Up to 80% of untreated patients may continue to experience episodes.

• Demographics:

  • There are no correlations found between particular ethnicity, socio-economic class, or lifestyle factors and the occurrence of depression.

Depression is Serious

• Hospitalization:

  • It is the most common diagnosis associated with psychiatric hospitalization.

• Suicide Risk:

  • Lifetime risk of suicide varies by treatment setting:

  • 2% in outpatients with Major Depressive Disorder (MDD).

  • 4% in inpatients with MDD.

  • 8% in inpatients with suicidal ideation or attempts.

• Mortality Rate:

  • Associated with increased mortality rates in individuals aged 50 years and older.

• Chronic Medical Conditions:

  • Correlated with worse outcomes in conditions such as diabetes mellitus.

What Does Depression Look Like?

• Key Symptoms:

  • Depressed mood and/or anhedonia (loss of interest or pleasure) are hallmark symptoms.

• Variability in Presentation:

  • Some patients may appear:

  • Sad, guilt-ridden, and hopeless.

  • Nervous, irritable, or agitated.

  • Complaining of somatic problems.

  • Psychotic Symptoms:

  • Depression can accompany psychotic symptoms in some cases.

Diagnosis of Major Depressive Disorder (MDD)

• DSM-IV Criteria:

  • Must meet 5 or more of the following criteria, with at least 1 being either depressed mood or anhedonia:

  • Depressed mood

  • Anhedonia

  • Weight loss or gain

  • Insomnia or hypersomnia

  • Psychomotor agitation

  • Fatigue or decreased energy

  • Feelings of worthlessness

  • Decreased concentration

  • Recurrent thoughts of death

  • Symptoms must cause significant distress or impair function.

  • Not better accounted for by bereavement following the loss of a loved one.

  • Symptoms must persist for at least 2 weeks.

SIG E CAPS

• A mnemonic for remembering key symptoms of depression:

  • Sleep disturbances

  • Interest loss (anhedonia)

  • Guilt

  • Energy loss

  • Concentration difficulties

  • Appetite changes

  • Psychomotor agitation or retardation

  • Suicidal thoughts.

Pathophysiology of Depression

• Etiology:

  • Not fully understood, but likely involves a combination of:

  • Genetic Predisposition:

    • 46% concordance rate among monozygotic twins vs. 20% rate among dizygotic twins.

    • Genetic differences in receptor and transporter expression and function.

  • Environmental Influences:

    • Adverse life experiences can lead to mood disorders.

  • Biological Factors:

    • Involves biogenic amines (Norepinephrine - NE, Serotonin - 5HT, Dopamine - DA).

    • Non-monoamine compounds (such as Corticotropin-Releasing Factor - CRF).

Biogenic Amine Theory

• Neurotransmitter Overview:

  • Neurotransmitters are chemical substances released from neurons that transmit nerve impulses across synapses.

  • Three primary neurotransmitters implicated in depression (the monoamines):

  • Serotonin (5HT)

  • Norepinephrine (NE)

  • Dopamine (DA).

Biogenic Amine Theory Continued

• Monoamine Reuptake Transporters:

  • Responsible for removing neurotransmitters (NTs) from the synapse.

  • Inhibition of these transporters increases NT levels in the synapse, with specific transporters for 5HT, NE, and DA.

• Monoamine Oxidase:

  • This enzyme metabolizes monoamines, resulting in decreased NT levels.

  • Inhibition of monoamine oxidase increases NT levels.

Treatment Approaches

• Pharmacotherapy:

• Psychotherapy:

  • Cognitive Behavioral Therapy (CBT)

  • Interpersonal Therapy

• Electroconvulsive Therapy (ECT).

Pharmacotherapy

• Antidepressant Usage Data:

  • Depictions of trends in antidepressant prescriptions over the years (1988 to 2002).

  • Notable drugs include:

  • Sertraline HCL

  • Paroxetine HCL

  • Fluoxetine HCL

  • Citalopram HBR

  • Bupropion HCL

  • Venlafaxine HCL.

Potential Drug Targets

• Transporters:

  • Serotonin transporter

  • Norepinephrine transporter

  • Dopamine transporter

• Receptors:

  • NE receptors

  • 5-HT receptors

• Enzymes:

  • Monoamine oxidase.

Types of Antidepressants

• **Selective Serotonin Reuptake Inhibitors (SSRIs) **

• **Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) **

• Atypical Antidepressants

• Tricyclic Antidepressants (TCAs)

• Monoamine Oxidase Inhibitors (MAOIs).

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Include:

  • Fluoxetine (Prozac®)

  • Sertraline (Zoloft®)

  • Paroxetine (Paxil®)

  • Citalopram (Celexa®)

  • Escitalopram (Lexapro®)

  • Fluvoxamine (Luvox®).

• Mechanism of Action (MOA):

  • Inhibit the serotonin transporter.

• Usage and Dosing:

  • Most frequently used antidepressants, typically dosed once a day, generally in the morning but may be taken at any time of day.

  • No conclusive data showing any one SSRI is more effective than others on a population basis.

SSRI Adverse Drug Reactions (ADRs)

• Related to increased serotonergic stimulation and nonselective receptor profiles:

  • Activation or sedation

  • Nausea

  • Sleep disturbances

  • Sexual side effects

  • Weight gain.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

• Inhibit the reuptake of 5HT and NE.

• Include:

  • Venlafaxine (Effexor): 5-HT reuptake inhibition across dosage range; NE reuptake inhibition occurs at doses greater than 200 mg/day (with dose-related increased blood pressure). Two formulations include XR (dosed once daily) and IR (dosed two to three times daily).

  • Duloxetine (Cymbalta): Balanced NE and 5HT reuptake inhibition across the dosage range; FDA approved for neuropathic pain associated with DM. Adverse effects similar to venlafaxine.

Other Antidepressants

• Bupropion (Wellbutrin®):

  • MOA: Inhibits DA and NE reuptake; FDA approved for smoking cessation (Zyban®); lowers seizure threshold; lower incidence of sexual side effects.

• Mirtazapine (Remeron®):

  • MOA: Enhances NE and 5HT activity; sedating with antihistaminic effects, useful for insomnia; weight gain.

• Trazodone (Desyrel):

  • MOA: Enhances 5HT activity; very sedating and primarily used for insomnia at doses <300 mg; nausea and GI upset can occur.

Tricyclic Antidepressants (TCAs)

• Examples include:

  • Amitriptyline (Elavil®)

  • Desipramine (Norpramin®)

  • Imipramine (Tofranil®)

  • Nortriptyline (Pamelor®).

• Mechanism of Action:

  • general inhibition of NE and 5HT reuptake; variable potency and selectivity; lethal in overdose (as little as 3x daily dose).

• Side Effects:

  • Many, including anticholinergic effects (dry mouth, dry eyes), orthostasis, sedation, weight gain, glucose dysregulation, and cardiac conduction issues.

Monoamine Oxidase Inhibitors (MAOIs)

• Reserved for treatment of resistant depression; requires dietary considerations to avoid foods high in tyramine (e.g., aged cheese, cured meats).

• Agents include:

  • Phenelzine (Nardil)

  • Selegiline (Eldepryl)

  • Tranylcypromine (Parnate).

Specialty Antidepressants

• Brexanolone (Zulresso®):

  • Indicated for postpartum depression; an IV infusion administered over 60 hours with continuous monitoring; known for possible excessive sedation; costs around $34,000.

• Zuranolone (Zurzuvae®):

  • Indicated for postpartum depression; a synthetic form of allopregnanolone; costs around $16,000 for treatment; warning against driving for 12 hours post-dose.

• Esketamine (Spravato):

  • Indicated for treatment-resistant depression; administered via nasal spray under treatment center supervision; known for sedation and abuse potential; costs between $650/treatment and $33,800/year.

Treatment Phases

• Phase 1: Acute Phase of Treatment:

  • Duration: 6-12 weeks; focus on symptom relief.

  • Goal: achieve remission.

• Phase 2: Continuation Phase of Treatment:

  • Duration: 4-9 months; bridged remission to recovery.

  • Full therapeutic doses maintained.

• Phase 3: Maintenance Phase of Treatment:

  • Continuation of antidepressant therapy for extended periods; not necessary for all, but beneficial for high-risk relapse patients.

Definitions in Treatment

• Response: Significant reduction in depressive symptoms without complete resolution.

• Remission: Complete resolution of depressive symptoms.

• Recovery: Sustained remission for at least 6 months.

• Relapse: Return of depressive symptoms within 6 months of achieving remission.

• Recurrence: Successive episode of MDD after recovery from an initial episode of MDD.

Choosing an Antidepressant

• On a population basis, all antidepressants are equally effective but individual response is generally unpredictable.

  • Background factors that influence choice:

  • Past history of response to particular agents.

  • Family history of responses.

  • Side effect profiles of different medications.

  • Comorbid conditions and potential interactions.

  • Cost considerations.

Treatment Goal

• The primary goal of treatment for MDD is remission, which results in improved functioning, a decreased risk of future episodes, and increases the interval before recurrence.

Managing Adverse Drug Reactions (ADRs)

• Insomnia:

  • Strategies include managing caffeine, considering morning dosing, and using short-term sleep medications.

• Anxiety:

  • May be transient, recommend minimizing caffeine, and gradual dosing increases.

• Nausea:

  • Start with low doses, consider administration with food, or a drug change if necessary.

• Sexual Side Effects:

  • Recommendations include observation for tolerance, dose reduction, and possibly switching the antidepressant to bupropion or mirtazapine.