What is the difference between combination and augmentation strategies in psychopharmacology for mood disorders?

Differentiating Combination from Augmentation Strategies in Psychopharmacology for Mood Disorders

Combination therapy refers to using two or more medications simultaneously to treat either multiple distinct disorders in the same patient or to address different symptom domains, while augmentation specifically means adding a second agent to an existing, partially effective medication to enhance its therapeutic effect for a single disorder. 1

Core Definitions and Clinical Applications

Combination Strategies

Combination therapy involves using medications together from the outset or adding medications to treat separate, co-occurring conditions. 1 The American Academy of Child and Adolescent Psychiatry identifies three primary combination scenarios:

• Treating multiple disorders simultaneously - For example, using a stimulant plus an SSRI for comorbid ADHD and anxiety, or an antipsychotic plus an SSRI for tics and OCD 1

• Addressing side effects of an effective primary agent - Such as adding benztropine for extrapyramidal symptoms caused by an antipsychotic that is otherwise controlling the target disorder 1

• Sculpting medication coverage - Using two formulations of the same medication class (e.g., short-acting and long-acting stimulants) to extend therapeutic coverage throughout the day 1

Augmentation Strategies

Augmentation specifically refers to adding a second medication to boost the effectiveness of a partially responsive first-line treatment for a single disorder. 1 The American College of Physicians defines this in the context of treatment-resistant depression:

• Adding lithium to ongoing antidepressant treatment represents a classic augmentation strategy for treatment-resistant depression 1

• Augmenting citalopram with bupropion or buspirone when the initial SSRI produces inadequate response 1

• Adding atypical antipsychotics (risperidone or aripiprazole) to SSRIs in treatment-resistant OCD, where approximately one-third of SSRI-resistant patients show clinically meaningful response 2

Key Distinguishing Features

Intent and Timing

• Combination therapy may be initiated simultaneously or sequentially but targets multiple problems or symptom domains 1

• Augmentation therapy is always sequential - it requires an initial adequate trial of monotherapy that produces partial but insufficient response 1, 2

Evidence Requirements

Before implementing either strategy, clinicians must verify that the initial treatment trial was adequate in dose, duration, and adherence. 1 For mood disorders, this typically means:

• 8-12 weeks at maximum tolerated doses for SSRIs in depression 2
• 12-24 months of maintenance therapy after achieving remission due to high relapse rates 2

Clinical Decision Algorithm

Step 1: Assess Treatment Adequacy

• Confirm the patient received adequate dose and duration of initial monotherapy 1
• Verify medication adherence was satisfactory 1
• Rule out that symptoms represent psychosocial stressors rather than biological illness progression 1

Step 2: Identify the Clinical Scenario

If treating multiple distinct disorders: Use combination therapy targeting each condition separately 1

If treating inadequate response to monotherapy for a single disorder: Consider augmentation strategies 1

If managing side effects of an otherwise effective medication: This represents combination therapy for tolerability 1

Step 3: Select the Appropriate Strategy

For augmentation in treatment-resistant depression:

• Adding bupropion or buspirone to ongoing SSRI therapy shows comparable efficacy, though bupropion may reduce depression severity more than buspirone 1
• Augmenting with cognitive therapy produces larger effect sizes than antipsychotic augmentation 2
• Discontinuation due to adverse events is lower with bupropion than buspirone 1

For augmentation in treatment-resistant OCD:

• Risperidone and aripiprazole have the strongest evidence for SSRI-resistant OCD 2
• N-acetylcysteine and memantine represent alternative glutamatergic augmentation options 2
• Adding CBT to pharmacotherapy shows larger effect sizes than antipsychotic augmentation 2

Critical Pitfalls to Avoid

Inappropriate Combination of Same-Class Medications

There is limited evidence supporting the use of two antidepressants or two antipsychotics as an initial treatment approach or specific endpoint. 1 The American Academy of Child and Adolescent Psychiatry specifically warns against:

• Using two antidepressants to "cover neurotransmitter bases" based on theoretical mechanisms 1
• Combining medications from the same class without empirical support 1
• The exception is bipolar disorder, where data support using two mood stabilizers in adults with preliminary support in children 1

Misattributing Psychosocial Stressors as Biological Symptoms

Clinicians must distinguish between symptoms representing biological illness progression versus behavioral reactions to psychosocial stressors. 1 For example:

• Irritability during recovery from major depression may reflect challenges returning to previous functioning rather than persistent mood disorder 1
• Such cases require psychosocial interventions rather than medication additions 1

Monitoring Requirements for Augmentation

When using antipsychotic augmentation, mandatory monitoring includes:

• Weight gain, blood glucose, and lipid profiles for metabolic side effects 2
• Assessment for serotonin syndrome when combining serotonergic medications 2, 3

Switching Versus Augmentation

Switching to a different medication represents an alternative to augmentation when initial monotherapy fails. 1 The American College of Physicians found:

• No significant difference in response or remission when switching between SSRIs (bupropion vs. sertraline vs. venlafaxine) 1
• No difference in response or remission when switching to cognitive therapy versus switching to another SSRI 1
• Consider switching to a different SSRI or SNRI if augmentation strategies fail 2