What are the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommendations for a patient who has failed two trials of Selective Serotonin Reuptake Inhibitors (SSRIs)?

CANMAT Recommendations After Two Failed SSRI Trials

Critical Finding

The provided evidence does not contain specific CANMAT (Canadian Network for Mood and Anxiety Treatments) guidelines for managing patients who have failed two SSRI trials. However, based on the highest quality available evidence addressing this clinical scenario, I can provide evidence-based recommendations for treatment-resistant depression after two SSRI failures.

Definition of Treatment Failure

Before proceeding, confirm that both SSRI trials were truly adequate:

• Minimum dose: Each SSRI should have been prescribed at the minimum licensed dose (or equivalent to 600mg chlorpromazine daily) 1
• Minimum duration: Each trial should have lasted at least 4-6 weeks at therapeutic dose 1
• Different mechanisms: The two SSRIs should ideally have different mechanisms of action, though this is less critical within the SSRI class 1

Primary Treatment Strategy: Switch to Non-SSRI Antidepressant

After two failed SSRI trials, switching to a non-SSRI antidepressant (bupropion, venlafaxine, or mirtazapine) provides superior remission rates compared to trying a third SSRI 2.

Evidence Supporting This Approach:

• Remission rates: 28% with non-SSRI switch versus 23.5% with another SSRI (statistically significant, p=0.007) 2
• Number needed to treat: 22 patients need to switch to a non-SSRI rather than another SSRI to obtain one additional remitter 2
• While this NNT is modest, it represents a clinically meaningful advantage given the large population affected 2

Specific Medication Options:

Option 1: Venlafaxine (SNRI)

• Shows modest benefit over SSRIs in meta-analysis 2
• In the STAR*D trial, venlafaxine achieved 24.8% remission rate after SSRI failure 3
• May be particularly beneficial for severely depressed inpatients 4

Option 2: Bupropion (NDRI)

• Achieved 21.3% remission rate in STAR*D after SSRI failure 3
• Different mechanism (norepinephrine-dopamine reuptake inhibitor) provides theoretical advantage 3
• Lower discontinuation due to adverse events compared to buspirone when used as augmentation 1

Option 3: Sertraline (if switching within SSRI class)

• If clinical factors favor staying within SSRI class, sertraline achieved 17.6% remission rate in STAR*D 3
• No significant difference in outcomes between bupropion, sertraline, and venlafaxine in head-to-head comparison 3

Treatment Duration for Second-Line Therapy

A 12-week trial duration is necessary to capture the maximum number of responders after switching antidepressants 5.

Timeline Expectations:

• Only 20% of patients remit after switching from a failed SSRI 5
• Half of responses occur after 6 weeks of treatment 5
• Two-thirds of remissions occur after 6 weeks 5
• 33% of all responses occur after ≥9 weeks of treatment 5
• Early predictor: Patients with ≥20% symptom reduction by week 2 are 6 times more likely to eventually respond or remit 5

Alternative Strategy: Augmentation

If switching is not preferred, augmentation of the current SSRI with another agent is an option:

Augmentation with bupropion or buspirone:

• No significant difference in response or remission rates between bupropion and buspirone augmentation 1
• Bupropion shows greater reduction in depression severity 1
• Bupropion has lower discontinuation rates due to adverse events 1

Psychotherapy Considerations

Switching to or augmenting with cognitive behavioral therapy (CBT) shows equivalent outcomes to medication switches 1:

• No difference in response or remission when switching to CBT versus switching to another antidepressant 1
• No difference when augmenting with CBT versus augmenting with another medication 1

Critical Caveats

Do Not Abruptly Discontinue SSRIs:

• Risk of SSRI withdrawal syndrome and psychiatric decompensation 6
• The underlying psychiatric condition (depression, anxiety, OCD) significantly impacts morbidity and quality of life 6

Realistic Expectations:

• More than 50% of patients achieve no meaningful benefit with a second-step switch 5
• Overall remission rates remain modest (20-28%) regardless of strategy 5, 2
• Number of previous treatment failures negatively correlates with treatment outcome 7

Treatment Resistance Threshold:

• After two adequate antidepressant failures with different mechanisms, the patient meets criteria for treatment-resistant depression (TRD) 1
• This may warrant consideration of specialized treatments beyond standard antidepressant switches 1