What medication can be added to amitriptyline (tricyclic antidepressant) and modafinil (wakefulness promoter) to help with Obsessive-Compulsive Disorder (OCD) symptoms?

Medication Augmentation for OCD with Amitriptyline and Modafinil

For a patient already on amitriptyline (TCA) and modafinil who needs additional medication for OCD symptoms, an SSRI such as sertraline should be added as first-line treatment, with careful monitoring for serotonin syndrome due to the combination with amitriptyline. 1

First-Line Augmentation Options

SSRI Addition

• SSRIs are the first-line pharmacological treatment for OCD according to the American College of Physicians and American Psychiatric Association 1
• Sertraline is extensively studied at higher doses for OCD (50-200 mg/day) and would be the preferred SSRI option 1
• Fluoxetine (20-60 mg/day) is another well-established option 1
• Fluvoxamine has demonstrated efficacy but may have more side effects than sertraline 1

Important Cautions

• When adding an SSRI to amitriptyline, there is significant risk of serotonin syndrome and increased blood levels of both medications 2
• Start with lower doses than usual and titrate slowly while monitoring for signs of serotonergic toxicity
• Consider reducing amitriptyline dose when adding the SSRI
• Clinical improvement typically begins by week 6, with maximal improvement by week 12 1

Second-Line Augmentation Options

If SSRI addition is ineffective or not tolerated, consider:

Antipsychotic Augmentation

• Risperidone or aripiprazole have the strongest evidence for OCD augmentation 2, 1
• Only about one-third of patients with SSRI-resistant OCD show clinically meaningful response to antipsychotic augmentation 2
• Requires careful monitoring for metabolic side effects and weight gain

Glutamatergic Agents

• N-acetylcysteine has the largest evidence base as a glutamatergic augmentation agent (three out of five randomized controlled trials showed superiority to placebo) 2, 1
• Memantine has demonstrated efficacy in several trials for treatment-resistant OCD 2, 1
• Other options include lamotrigine, topiramate, and riluzole 2, 1

Treatment Algorithm

1. First step: Add sertraline starting at 25-50 mg/day, gradually increasing to 50-200 mg/day over 4-6 weeks
2. If partial response after 12 weeks: Increase to maximum tolerated dose
3. If inadequate response after 12 weeks at maximum dose:
   • Option A: Switch to a different SSRI (fluoxetine or fluvoxamine)
   • Option B: Add N-acetylcysteine (most evidence-based glutamatergic agent)
   • Option C: Add risperidone or aripiprazole (start with low doses)
4. If still inadequate response: Consider memantine augmentation

Monitoring and Side Effects

• Monitor closely for signs of serotonin syndrome (confusion, agitation, muscle rigidity, hyperthermia)
• Watch for suicidal ideation, especially in the first months and after dose adjustments 1
• Be alert for behavioral activation/agitation, which is more common in anxiety disorders 1
• Assess for drug interactions between all three medications (amitriptyline, modafinil, and the added agent)

Non-Pharmacological Considerations

• Consider adding cognitive-behavioral therapy with exposure and response prevention (CBT-ERP), which has larger effect sizes than pharmacological therapy alone 1
• For very treatment-resistant cases, neuromodulation approaches like deep repetitive TMS or rTMS targeting the supplementary motor cortex or dorsolateral prefrontal cortex may be considered 2, 1

Common Pitfalls to Avoid

• Inadequate dosing of the SSRI (OCD often requires higher doses than depression)
• Premature discontinuation before full effect is achieved (minimum 12 weeks)
• Failure to recognize partial response
• Insufficient monitoring for serotonin syndrome with the amitriptyline-SSRI combination