What is the recommended formulation, immediate release (IR) or extended release (XR), for initiating amphetamine salt combination therapy in a patient with Attention Deficit Hyperactivity Disorder (ADHD)?

Amphetamine Salt Combination: IR vs XR for ADHD Initiation

Start with immediate-release (IR) amphetamine salts at 2.5-5 mg twice daily for initial titration, then convert to extended-release (XR) formulation once optimal dosing is established, or alternatively start directly with XR 10 mg once daily in the morning if adherence to multiple daily doses is a concern. 1, 2

Rationale for IR-First Approach

The American Academy of Child and Adolescent Psychiatry's practice parameters establish that patients should be started on immediate-release formulations to allow flexible dose titration and identification of the optimal therapeutic dose with minimal side effects. 1

Initial Dosing Strategy with IR

• Start with 2.5 mg IR twice daily (after breakfast and lunch) for children, or 5 mg IR twice daily for adults 1
• Increase by 5 mg increments weekly based on standardized ADHD rating scales from teachers, parents, or the patient 1
• Continue titration until symptoms resolve or side effects emerge, typically reaching 10-60 mg total daily dose for methylphenidate-equivalent dosing 1
• A third afternoon dose can be added at clinician's discretion to cover homework and social activities 1

Advantages of IR for Initial Titration

• Allows precise identification of minimum effective dose by testing multiple dose levels (2.5,7.5,10 mg) with weekly assessments 1
• Enables flexible timing adjustments to minimize side effects like appetite suppression at dinner or sleep onset delay 1
• Permits "forced titration" trials where patients systematically try all dose levels to identify optimal response 1
• Children may require only once-daily dosing with amphetamines, which can be determined during IR titration 1

Converting to XR After Titration

Once the optimal total daily IR dose is established, conversion to XR formulation improves adherence by eliminating in-school dosing. 1

Conversion Method

• Add morning and noon IR doses together to determine XR dose 1
• Example: If taking 10 mg IR morning + 10 mg IR noon = 20 mg XR once daily in morning 1
• Can combine XR with supplemental IR doses for fine-tuning (e.g., 20 mg XR morning + 5 mg IR morning and noon) 1

Alternative: Direct XR Initiation

For patients where adherence to multiple daily doses is problematic, starting directly with XR 10 mg once daily in the morning is acceptable. 1, 2, 3

XR-First Dosing Protocol

• Start with 10 mg XR once daily in the morning 1, 2, 3
• Titrate by 5 mg weekly increments based on clinical response 2, 4
• Maximum dose 40-50 mg daily for adults 2, 3
• Morning administration is critical to minimize sleep disturbances 2, 4, 3

XR Pharmacokinetic Advantages

• Provides rapid onset within 1.5 hours with 12-hour duration of coverage 5
• Dual-release mechanism: immediate-release pellets provide initial effect, delayed-release pellets activate at 4 hours 5
• Eliminates need for in-school medication administration, reducing stigma and improving adherence 1

Monitoring During Initiation

Regardless of formulation chosen, systematic monitoring is essential:

• Baseline assessment: blood pressure, pulse, height, weight 1, 2
• Weekly contact (phone acceptable) during titration with monthly in-person visits 1, 2
• Use standardized ADHD rating scales, not subjective reports alone 1
• Assess for common side effects: anorexia, insomnia, headache, irritability 1, 2

Critical Pitfalls to Avoid

• Starting at too high a dose causes unnecessary side effects and medication refusal 2, 4, 3
• Not allowing one full week between dose increases prevents accurate response assessment 2, 4
• Failing to use validated rating scales leads to subjective, unreliable dose adjustments 1
• Afternoon/evening dosing causes insomnia—always dose in morning 2, 4, 3
• Continuing to increase beyond maximum dose (40-50 mg) when ineffective—switch medications instead 2, 4, 3

Special Population Considerations

Children <25 kg

• Do not exceed 10 mg single doses 2
• Use more conservative titration schedule 1

Older Adults

• More sensitive to both therapeutic and adverse effects 3
• Consider increasing by 5 mg every 2 weeks instead of weekly 3
• Monitor cardiovascular parameters more closely 3

Pregnancy/Lactation

• If treatment necessary, XR formulation starting at 10 mg daily with 5 mg weekly titration up to 50 mg 1
• Monitor infant for irritability, insomnia, feeding difficulty if breastfeeding 1

Evidence Quality Note

The 2002 American Academy of Child and Adolescent Psychiatry guidelines 1 remain the definitive practice parameters for stimulant initiation, with more recent 2024-2025 consensus 1, 2, 4, 3 supporting either IR-first or direct XR approaches based on adherence considerations. Research studies 5, 6, 7, 8, 9 consistently demonstrate efficacy and safety of both formulations, with XR showing 12-hour coverage and high effect sizes (0.8) in adults 6.