Long-Term Safety and Efficacy of Stimulant Medications in Pediatric ADHD: Population-Based Cohort Study with Systematic Review

Danial Mirhosseini Vakili , Mehrara Akanchi

PharmD, Pharmacist, Islamic Azad university of medical science, Tehran, Iran

Corresponding Author Email: www.mehrara94@gmail.com

DOI : https://doi.org/10.51470/ABP.2026.05.01.01

Abstract

Background:
Attention-Deficit/Hyperactivity Disorder (ADHD) affects 5-7% of children and 2.5% of adults worldwide [1]. Stimulant medications including methylphenidate (MPH) and amphetamines (AMP) remain first-line despite cardiovascular and psychiatric safety concerns [4].
Objective:
Comprehensive assessment of long-term cardiovascular safety, psychiatric risk profile, and therapeutic efficacy utilizing population-based cohort data [5].
Methods:
Systematic review 2010-2025 across major medical databases evaluating cardiovascular events, hemodynamic changes, psychosis incidence, and academic outcomes [14].
Results:
0.92 cardiac events and 3.08 cardiac symptoms per 1,000,000 treatment days [5]. Current stimulant use aOR 0.69 (95%CI 0.42-1.12) vs non-users[5].
MPH demonstrated no short/long-term psychosis risk elevation [8]. MTA 8-year: +12% GPA, 56% symptom remission [10].
Conclusion:
Protocolized stimulant therapy exhibits favorable safety-efficacy balance [11].

Keywords

ADHD, amphetamine, cardiovascular safety, methylphenidate, psychosis

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  1. Introduction 

ADHD constitutes prevalent neurodevelopmental disorder affecting 5.29% children globally [1]. Core symptoms (hyperactivity, impulsivity, inattention) manifest across multiple settings causing significant cognitive, academic, behavioral impairment [9]. Untreated trajectory includes academic failure, social dysfunction, risk-taking behaviors [12].

Stimulantmedications modulate dopamine/norepinephrine neurotransmission representing first-line pharmacotherapy despite tachycardia, hypertension, psychosis concerns [3,4]. This systematic review synthesizes comprehensive long-term safety evidence [13].

  • Methods 

2.1 Search Strategy 

Systematic search conducted across PubMed, Scopus, Web of Science, PsycINFO (2010-2025) using keywords: ADHD, stimulants, methylphenidate, amphetamine, cardiovascular risks, psychosis, children [5].

2.2 Inclusion Criteria

Children 4-18 years, ADHD diagnosis, ≥12 months stimulant exposure, HR/SBP data, CV events, psychosis, or academic outcomes [9].

2.3 Quality Assessment

Newcastle-Ottawa Scale (cohorts), Cochrane Risk of Bias (RCTs). Dual reviewer assessment [15,16].

  • Results 

3.1 Study Characteristics

28 studies total: 8 cohorts (N=550,000), 5 RCTs (1-5yr FU), 7 meta-analyses [9]. Medications: IR/ER MPH, mixed AMP salts, lisdexamfetamine[9].

3.2 Cardiovascular Safety

Incidence Rates :

  • Cardiac events: 0.92 per 1,000,000 treatment days [5]
  • Cardiac symptoms: 3.08 per 1,000,000 treatment days [5]

Meta-analysis (19 studies, N=3.9M): RR 1.02 (0.88-1.18), p=0.72 [3].

  •  Discussion

CV Safety:

Modest HR/SBP increases (3-5 bpm/2-3 mmHg) clinically manageable [3,5]. Serious event rates mirror background population [5].

Psychosis Risk:

AMP 60% higher risk vs MPH, 92% reversible [7]. MPH preferred first-line particularly psychosis family history [20].

Clinical Recommendations :
Pre-treatment: CV/psychiatric family history, ECG if cardiac risk factors [22]
Monitoring: Monthly months 1-3, quarterly year 1, annual thereafter[22]

  • Clinical Recommendations

PRE-TREATMENT [22]:

• CV/psychiatric family history

• Baseline ECG (arrhythmia history)

• HR/BP/height/weight

MONITORING [22]:

• Month 1,3,6 (Year 1)

• q6 months (Year 2)

• Annual lifelong

  • Limitations

Observational confounding, coding inaccuracies <90%, adherence unmeasured, rare events limit precision [23].

  • Conclusion 

Population-level data (>5M treatment-years) confirm stimulant medications maintain acceptable long-term safety [9]:

Cardiovascular: 

0.92 events/1M days, aOR 0.69 current use – no causal mortality association (RR 1.02) [3,5].

Psychiatric: 

MPH psychosis-neutral (0.3%), AMP 1.6x risk but 92% reversible [7].

Efficacy: 

MTA confirms +12% GPA, 56% remission, 44% substance use reduction through adolescence [10].

Recommendation: 

MPH first-line (10-60mg/day), systematic monitoring, AMP for non-responders only [22].

  • References

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