How do you differentiate and treat Major Depressive Disorder (MDD) versus Persistent Depressive Disorder (PDD) in terms of diagnosis, medication (such as Selective Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine and sertraline), and psychotherapy (like Cognitive Behavioral Therapy (CBT))?

Differentiating and Treating Major Depressive Disorder versus Persistent Depressive Disorder

Diagnostic Differentiation

The key distinction between MDD and Persistent Depressive Disorder (PDD, formerly dysthymia) is duration: MDD requires at least 2 weeks of symptoms, while PDD requires chronic depressive symptoms lasting at least 2 years. 1

MDD Diagnostic Criteria

• Requires at least 5 symptoms during a 2-week period, including either depressed mood or anhedonia (loss of pleasure/interest), plus additional symptoms such as insomnia/hypersomnia, psychomotor changes, fatigue, and changes in appetite or weight 1
• Symptoms must cause significant functional impairment in work, social, or other important areas 1
• Use the PHQ-9 (cutoff ≥8) or Hamilton Depression Rating Scale to assess severity and monitor treatment response 1

PDD Diagnostic Criteria

• Chronic depressive symptoms present more days than not for at least 2 years in adults (1 year in children/adolescents)
• During this period, the patient is never without symptoms for more than 2 months at a time
• May have fewer symptoms than MDD but the chronicity defines the disorder
• Often has insidious onset and persistent course

Treatment Approach by Severity

Mild MDD

Start with cognitive behavioral therapy (CBT) alone as monotherapy. 1, 2

• CBT has equivalent effectiveness to second-generation antidepressants for mild depression with moderate-quality evidence 1
• Behavioral activation within CBT specifically targets anhedonic symptoms by re-engaging patients with pleasurable activities 3
• Avoid premature pharmacotherapy in mild cases where psychotherapy alone is sufficient 1

Moderate to Severe MDD

Initiate either CBT or a second-generation antidepressant (SSRI/SNRI) as monotherapy, with combination therapy reserved for severe cases or inadequate response. 1, 2

• Both CBT and second-generation antidepressants have equivalent effectiveness as first-line treatments based on moderate-quality evidence 1
• For severe MDD, combination therapy (CBT + antidepressant) produces superior outcomes compared to monotherapy, with remission rates nearly doubling (57.5% vs 31.0%, P < 0.001). 1
• Select SSRIs (fluoxetine, sertraline, escitalopram) or SNRIs based on adverse effect profiles, cost, and patient-specific symptoms 1
• Sertraline, fluoxetine, and other second-generation antidepressants show no substantial differences in efficacy for treating MDD 4

Persistent Depressive Disorder

Treat PDD with the same pharmacologic and psychotherapeutic approaches as MDD, but anticipate longer treatment duration due to the chronic nature of the disorder.

• Second-generation antidepressants (SSRIs/SNRIs) are first-line pharmacotherapy 1
• CBT is equally effective and should be strongly considered, particularly given the chronic nature requiring long-term management 1
• Combination therapy may be more beneficial given the chronicity and treatment resistance often seen in PDD 1

Pharmacotherapy Selection Algorithm

First-Line SSRI/SNRI Selection

• Sertraline or escitalopram are preferred initial choices due to favorable tolerability profiles and lack of sedating properties. 1
• Fluoxetine, paroxetine, and citalopram are equally effective alternatives with no significant differences in efficacy 4
• SNRIs (venlafaxine, duloxetine) may be slightly more effective for severe depression but carry higher rates of nausea and vomiting 1
• For patients with prominent anxiety symptoms, all SSRIs show similar efficacy, though limited evidence suggests venlafaxine may be superior to fluoxetine 4
• For patients with insomnia, consider that nefazodone showed improvement over fluoxetine in sleep scores, though this is limited evidence 4

Critical Prescribing Considerations

• Monitor for suicidality closely, especially during the first few weeks of treatment or when changing doses, as antidepressants may increase suicidal thoughts in young adults. 5
• Assess response within 1-2 weeks of initiation, monitoring for therapeutic effects, adverse effects, and suicidality 1
• If inadequate response by 6-8 weeks, modify treatment through dose adjustment, switching agents, or augmentation 1
• Sertraline inhibits CYP2D6 and may increase plasma concentrations of co-administered drugs metabolized by this pathway, requiring dose adjustments 5
• Avoid combining SSRIs with MAOIs (requires 2-week washout period) due to risk of life-threatening serotonin syndrome. 5
• Monitor for serotonin syndrome when combining with triptans, tramadol, or other serotonergic drugs 5

Treatment Duration

Acute Phase (6-12 weeks)

• Continue treatment until remission is achieved (≥50% reduction in severity scores) 1
• Therapeutic effects typically require 4-6 weeks to manifest fully 1

Continuation Phase (4-9 months minimum)

• Continue antidepressant treatment for at least 4-9 months after satisfactory response for first episodes. 1
• This continuation phase is critical to prevent relapse, supported by meta-analysis of 31 randomized trials 4

Maintenance Phase (≥1 year)

• For recurrent episodes or PDD, continue treatment for ≥1 year or longer to prevent relapse. 1
• PDD typically requires indefinite maintenance therapy given its chronic nature

Second-Line Treatment for Inadequate Response

If no response to initial SSRI/SNRI after 6-8 weeks at adequate dose, choose one of the following strategies: 1, 2

Option 1: Switch to CBT or Augment with CBT

• Switching to or augmenting with CBT is supported by low-certainty evidence 2
• Particularly effective when combined with continued pharmacotherapy in severe cases 1

Option 2: Switch Antidepressants or Augment Pharmacologically

• Switch to a different second-generation antidepressant from a different class (e.g., SSRI to SNRI or vice versa) 2
• Augmentation options include adding a second antidepressant, atypical antipsychotic, lithium, or thyroid hormone 6
• Combining atypical antipsychotics with traditional antidepressants may increase remission rates 6

Common Pitfalls to Avoid

• Do not discontinue treatment prematurely before 4-9 months after achieving remission, as this dramatically increases relapse risk. 1, 3
• Do not use inadequate doses or insufficient duration (minimum 4-6 weeks at therapeutic dose) before declaring treatment failure. 1
• Do not ignore accompanying symptoms: assess for anxiety, insomnia, pain, and psychomotor changes that may influence medication selection 4, 1
• For patients with prominent anhedonia, avoid relying solely on SSRIs as first-line agents, as they show limited efficacy for this symptom and may worsen it. 3
• Do not combine SSRIs with NSAIDs, aspirin, or warfarin without careful monitoring, as this increases bleeding risk 5
• Do not fail to screen for bipolar disorder before initiating antidepressants, as this may precipitate manic episodes 5