Is it reasonable to discontinue duloxetine (Cymbalta) 60mg and start pregabalin (Lyrica) for anxiety, while increasing vyvanse (lisdexamfetamine) to 40mg for attention deficit hyperactivity disorder (ADHD) in a patient with a history of inadequate response to escitalopram (Lexapro) and sertraline (Zoloft), who exercises daily, eats a healthy diet, and has consistent sleep patterns?

Discontinuing Duloxetine and Starting Pregabalin While Increasing Vyvanse for ADHD

Your proposed plan is reasonable with important modifications: taper duloxetine over 10-14 days (not abrupt discontinuation), consider pregabalin as a viable alternative for your somatic anxiety symptoms, and increase Vyvanse to 40 mg with the understanding that many patients require higher doses for therapeutic effect.

Duloxetine Discontinuation Strategy

You must taper duloxetine gradually over 10-14 days minimum, not stop it abruptly. 1 After only 1 month of treatment at 60 mg daily, you still require a proper taper to minimize withdrawal symptoms, which can include dizziness, fatigue, nausea, headaches, anxiety, irritability, and sensory disturbances. 2, 1

• The standard approach is to reduce the dose incrementally over at least 2 weeks for anyone treated longer than 3 weeks. 2, 1
• Given your lack of response after a month, discontinuation is appropriate—duloxetine typically shows symptom improvement within the first few weeks, and you've passed that window without benefit. 1
• Critical caveat: Exercise caution when combining duloxetine with stimulants like Vyvanse during the taper period, as both are serotonergic agents. 2 Monitor closely for any signs of serotonin syndrome (agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity).

Pregabalin as an Alternative for Somatic Anxiety

Pregabalin represents a strong evidence-based option for your treatment-resistant anxiety, particularly given your somatic/physical symptoms and failure to respond to three different antidepressants. 3, 4, 5

• Pregabalin has a rapid onset of action (typically within 1 week), which is substantially faster than SSRIs/SNRIs that require 2-4 weeks. 3, 4, 6
• It demonstrates efficacy against both psychic (emotional) and somatic (physical) anxiety symptoms—particularly relevant for your somatic restlessness. 4
• In a large network meta-analysis of 89 trials with 25,441 patients, pregabalin showed robust efficacy (mean difference -2.79 on Hamilton Anxiety Scale) with good tolerability. 5
• A head-to-head study found pregabalin comparable to sertraline in efficacy but with faster onset. 3
• Pregabalin is considered a first-line agent for generalized anxiety disorder alongside SSRIs/SNRIs by the World Federation of Societies of Biological Psychiatry. 4

Common side effects to anticipate: dizziness, somnolence, and weight gain, typically mild-to-moderate and transient. 4, 6 The abuse potential is low, and withdrawal risk is minimal when discontinued gradually over 1 week. 4

Vyvanse Dose Optimization for ADHD

It is extremely common to not achieve therapeutic response at 40 mg Vyvanse—many patients require titration to higher doses for adequate ADHD control. 2

• Your inability to determine if 40 mg worked previously suggests it was likely subtherapeutic for you.
• The standard approach is to start at a dose and increase gradually until you achieve optimal benefit or reach maximum tolerated dose. 2
• Use intermittent dosing strategically: Since you're concerned about medication exposure and stimulants have rapid onset/offset, consider taking Vyvanse only on days when ADHD symptoms most impair your functioning. 2 This allows you to assess efficacy more clearly.
• Continue your excellent non-pharmacologic strategies (consistent sleep, daily vigorous exercise, healthy diet)—these enhance stimulant efficacy. 2

Timing and Sequencing Considerations

Begin the duloxetine taper immediately, start pregabalin after completing the taper (or during the final days), and increase Vyvanse concurrently. 2

• When discontinuing one medication for anxiety and starting another, the general principle is to complete or nearly complete the taper of the ineffective medication before introducing the new one. 2
• This approach allows you to clearly attribute any new symptoms or benefits to the appropriate medication.
• Monitor carefully for the first 24-48 hours after any dose changes, particularly given the combination of a stimulant with pregabalin. 2

Critical Safety Monitoring

• Watch for any signs of serotonin syndrome during the duloxetine taper while on Vyvanse (though risk is low with tapering). 2
• Monitor for increased anxiety or agitation when increasing Vyvanse—stimulants can initially worsen anxiety symptoms. 2
• Pregabalin's sedating effects may counterbalance any stimulant-induced anxiety, but start at a low dose and titrate gradually. 4
• Ensure you're gaining appropriate benefit from Vyvanse before pushing to higher doses—more is not always better, and higher doses increase side effects without necessarily improving efficacy. 2