Non-Stimulant ADHD Medication Comparison Table
Quick Reference Tool | PsychHQ
Source: Module 4, Non-Stimulant & Adjunct Pharmacotherapy | Last Updated: February 2026
FDA-Approved Non-Stimulants at a Glance
|
Atomoxetine (Strattera) |
Guanfacine XR (Intuniv) |
Clonidine XR (Kapvay) |
Viloxazine ER (Qelbree) |
| Class |
Selective NET inhibitor |
Selective α-2A agonist |
Non-selective α-2 agonist |
Serotonin-NE modulating agent (SNMA) |
| FDA Ages |
≥6 yrs + adults |
6–17 yrs |
6–17 yrs |
≥6 yrs + adults |
| Effect Size |
SMD −0.56 (Cortese 2018) |
SMD −0.59 (Hirota 2014) |
SMD −0.59 (Hirota 2014) |
MD 5.47 pts on ADHD-RS-5 (Yu 2024)† |
| Onset to Clinical Effect |
6–8 weeks (max 12–26 wks) |
2–4 weeks |
2–4 weeks |
1–2 weeks |
| Controlled Substance |
No |
No |
No |
No |
| Abuse Potential |
None |
None |
None |
None |
| Dosing Frequency |
QD or BID |
QD (bedtime) |
BID (higher dose at bedtime) |
QD |
| 24-Hour Coverage |
Yes, continuous at steady state (T1/2 ~5 hrs NM, ~24 hrs PM) |
Functionally yes (T1/2 ~18 hrs, QD dosing) |
Functionally yes with BID dosing (T1/2 ~12-16 hrs) |
Partial; T1/2 ~7 hrs but clinical effect may extend beyond PK window at steady state |
†Note on viloxazine effect size: The viloxazine value is a mean difference (MD) in ADHD-RS-5 total score points, not a standardized mean difference (SMD). It is not directly comparable to the SMD values listed for the other three medications. No large network meta-analysis has yet published an SMD for viloxazine alongside the older non-stimulants on a common scale. Based on available trial data, viloxazine's efficacy appears broadly comparable to other non-stimulants.
Dosing Quick Reference
Atomoxetine (Strattera)
| Population |
Starting Dose |
Target Dose |
Maximum Dose |
Key Notes |
| Children/adolescents ≤70 kg |
0.5 mg/kg/day |
1.2 mg/kg/day |
1.4 mg/kg/day or 100 mg |
Wait minimum 3 days (conservative: 7–14 days) before increase |
| Adolescents >70 kg / Adults |
40 mg/day |
80 mg/day |
100 mg/day |
Can split as 40 mg AM + 40 mg late PM if peak-dose nausea |
| Moderate hepatic impairment |
Reduce all doses to 50% |
— |
— |
Child-Pugh Class B |
| Severe hepatic impairment |
Reduce all doses to 25% |
— |
— |
Child-Pugh Class C |
| CYP2D6 poor metabolizers |
0.5 mg/kg/day |
Hold 4 full weeks before any increase |
— |
~10× higher drug exposure; ~5–7% of Europeans |
| On strong CYP2D6 inhibitors |
40 mg/day (>70 kg) |
Hold 4 weeks before increase |
80 mg/day if tolerated |
Fluoxetine, paroxetine, bupropion cause phenoconversion |
Guanfacine XR (Intuniv)
| Population |
Starting Dose |
Titration |
Target Dose |
Maximum Dose |
| Children 6–12 yrs |
1 mg QD |
↑ 1 mg/week |
0.05–0.12 mg/kg/day |
4 mg/day |
| Adolescents 13–17 yrs |
1 mg QD |
↑ 1 mg/week |
0.05–0.12 mg/kg/day |
7 mg/day |
| On strong CYP3A4 inhibitors |
Reduce dose by ~50% |
— |
— |
Ketoconazole, ritonavir, etc. |
| On strong CYP3A4 inducers |
May need to double dose |
— |
— |
Rifampin, carbamazepine, etc. |
Administration: Swallow whole, do NOT crush, chew, or break. Avoid high-fat meals (increases absorption). Dose at bedtime (peak ~5 hrs post-dose aligns with sleep). Optional: some clinicians dose in the AM for patients with prominent daytime behavioral issues, though bedtime dosing is standard.
Weight-based dosing note: Target dose is 0.05-0.12 mg/kg/day, so effective therapeutic doses are weight-dependent. A heavier younger child (e.g., 50 kg at age 10) may appropriately reach 4 mg (the 6-12 yr cap) while a lighter child of the same age may only need 2-3 mg. Titrate to clinical response within the mg/kg range, not just by age bracket.
Clonidine XR (Kapvay)
| Population |
Starting Dose |
Titration |
Dosing Split |
Maximum Dose |
| Children 6–17 yrs |
0.1 mg at bedtime |
↑ 0.1 mg/week total daily dose |
Split BID: higher portion at bedtime (e.g., 0.1 mg AM / 0.2 mg PM) |
0.4 mg/day |
Administration: No food effect, flexible timing relative to meals. Requires twice-daily dosing.
Clonidine IR for sleep: Clonidine IR (0.05-0.2 mg at bedtime) is commonly used off-label for stimulant-induced insomnia. In a chart review (Prince et al., 1996), 85% of children showed meaningful sleep improvement. The short duration of IR is actually an advantage here: sedation is concentrated in the first few hours, helping with sleep onset without significant morning hangover. The European ADHD Guidelines Group lists low-dose clonidine as a management option for stimulant-induced insomnia.
Viloxazine ER (Qelbree)
| Population |
Starting Dose |
Titration |
Target Dose |
Maximum Dose |
| Children 6–11 yrs |
100 mg QD |
↑ 100 mg/week |
200–400 mg/day |
400 mg/day |
| Adolescents 12–17 yrs |
200 mg QD |
↑ 200 mg/week |
200–400 mg/day |
400 mg/day |
| Adults 18+ |
200 mg QD |
↑ 200 mg/week |
200–600 mg/day |
600 mg/day (~36% need max) |
| Severe renal impairment (eGFR <30) |
100 mg QD |
↑ 50–100 mg/week |
— |
200 mg/day |
Administration: Can open capsule and sprinkle on applesauce (consume within 2 hrs) or pudding (within 15 min). Adults: dose in morning (insomnia common). Children: consider evening dosing if daytime somnolence occurs.
Side Effect Comparison
| Side Effect |
Atomoxetine |
Guanfacine XR |
Clonidine XR |
Viloxazine ER |
| Nausea/GI upset |
Common (children) |
Uncommon |
Uncommon |
Common |
| Decreased appetite |
Common |
Less common |
Less common |
Common |
| Somnolence/sedation |
Moderate |
21–51% |
~35% |
16% (children); rare (adults) |
| Insomnia |
Some adults |
Rare |
Rare |
23% (adults) |
| Hypotension |
Rare |
Dose-dependent (~1% symptomatic) |
More prominent |
Rare |
| Bradycardia |
Rare |
Dose-dependent |
More prominent |
Rare |
| HR/BP increase |
Modest increase |
Decrease |
Decrease |
Up to 31% transient HR increase (children) |
| Dry mouth |
Adults |
Some |
Some |
Less common |
| Erectile dysfunction |
Adults |
Rare |
Rare |
Rare |
| Weight effects |
Decreased appetite |
Neutral to mild gain |
Neutral to mild gain |
Decreased appetite |
Boxed Warnings and Serious Risks
| Risk |
Atomoxetine |
Guanfacine XR |
Clonidine XR |
Viloxazine ER |
| FDA Boxed Warning |
Suicidal ideation in pediatric patients (0.4% vs 0% placebo) |
None |
None |
Suicidal ideation (0.9% peds, 1.6% adults) |
| Hepatotoxicity |
Rare but serious (immune-mediated); stop immediately if jaundice/dark urine |
— |
— |
— |
| Rebound hypertension on discontinuation |
— |
YES. Taper 1 mg/3-7 days |
YES. Taper 0.1 mg/3-7 days |
— |
| Priapism |
Rare (urological emergency) |
— |
— |
— |
| MAOI contraindication |
Absolute (14-day washout) |
— |
— |
Absolute (14-day washout) |
Primary Metabolism
| Medication |
Primary Metabolic Pathway |
Key Enzyme |
Clinical Implication |
| Atomoxetine |
~97% hepatic via CYP2D6 to 4-hydroxyatomoxetine (active). Minimal renal excretion of parent drug |
CYP2D6 |
Highly susceptible to CYP2D6 genetic variation and drug interactions. Poor metabolizers get ~10x exposure |
| Guanfacine XR |
~50% hepatic via CYP3A4. ~30% renal excretion unchanged |
CYP3A4 |
Susceptible to CYP3A4 inducers/inhibitors. Adjust dose accordingly |
| Clonidine XR |
~50% hepatic (multiple pathways, not predominantly CYP-dependent). ~40-60% renal excretion unchanged |
Non-CYP hepatic + renal |
Relatively insulated from CYP drug interactions. Additive effects with CNS depressants are the main concern |
| Viloxazine ER |
Hepatic via multiple pathways (CYP1A2, CYP2D6, CYP3A4, UGT1A9, UGT2B15). NOT a CYP2D6 substrate |
Multiple (acts as strong CYP1A2 inhibitor) |
Predictable PK across populations. Main interaction risk is as a CYP1A2 inhibitor affecting other drugs |
Key Drug Interactions
| Medication |
Critical Interactions |
Clinical Rule |
| Atomoxetine |
CYP2D6 substrates. Fluoxetine, paroxetine, bupropion → 6–8× increase in ATX levels (phenoconversion). Absolute MAOI contraindication |
If on strong CYP2D6 inhibitor: cap at 40 mg/day × 4 weeks before any increase |
| Guanfacine XR |
CYP3A4 substrates. Strong 3A4 inducers (rifampin) ↓ levels → may need dose doubling. Strong 3A4 inhibitors ↑ levels → preemptive dose reduction |
Check CYP3A4 interaction before starting |
| Clonidine XR |
Additive sedation with CNS depressants. Additive hypotension with antihypertensives |
Monitor closely with any CNS depressant |
| Viloxazine ER |
Strong CYP1A2 inhibitor. Contraindicated with tizanidine, theophylline, duloxetine, clozapine. Caffeine interaction: dramatically prolongs caffeine half-life → jitteriness, insomnia, tremors. Absolute MAOI contraindication |
Limit caffeine to <300 mg/day. NOT a CYP2D6 substrate (advantage over atomoxetine) |
Pharmacogenomic Considerations
| Factor |
Atomoxetine |
Viloxazine |
| Key enzyme |
CYP2D6 (primary metabolism) |
NOT a CYP2D6 substrate |
| Poor metabolizers (PM) |
~5-7% Europeans; ~10x higher exposure, T1/2 ~24 hrs |
N/A, predictable PK |
| Intermediate metabolizers (IM) |
~42% East Asian (CYP2D610); ~35% African ancestry (CYP2D617) |
N/A |
| Ultrarapid metabolizers (UM) |
2-3% European; 20-29% East African, may need above-label doses |
N/A |
| Pharmacogenomic testing value |
High, directly changes dosing |
Low, not needed |
Clinical Scenario Selection Guide
| Clinical Scenario |
Preferred Non-Stimulant |
Rationale |
| Active SUD or high diversion risk |
Atomoxetine |
Zero abuse potential, non-controlled, 24-hr coverage; AACAP/CADDRA endorsed |
| Comorbid anxiety (primary, not secondary to ADHD) |
Atomoxetine or Viloxazine |
ATX: may reduce anxiety symptoms (Geller 2007). VLX: serotonergic activity provides mood/anxiety modulation |
| Comorbid mood lability / emotional dysregulation |
Viloxazine or Guanfacine XR |
VLX: dual NE + serotonin mechanism. GXR: alpha-2A strengthens prefrontal emotional regulation |
| Severe stimulant rebound irritability |
Guanfacine XR (adjunct) |
Smooths late-afternoon rebound; bedtime dosing provides overnight coverage |
| Stimulant-induced insomnia (refractory to behavioral interventions) |
Guanfacine XR or Clonidine XR (adjunct), or Clonidine IR 0.05-0.2 mg at bedtime |
Sedative peak at bedtime; treats residual ADHD + promotes sleep in one agent. Clonidine IR is an option when sleep is the primary target (short duration concentrates sedation at bedtime without morning hangover) |
| Comorbid tic disorder |
Guanfacine XR (adjunct or monotherapy) |
Reduces tics 31% while improving ADHD (Scahill 2001) |
| Severe hyperarousal / oppositional aggression |
Clonidine XR |
Broader receptor profile (α-2A/B/C + imidazoline) targets autonomic hyperarousal |
| Need for fastest onset |
Viloxazine |
Separation from placebo at Week 1–2 (vs 4–6 wks for ATX) |
| Need for 24-hour coverage without stimulant peaks/crashes |
Atomoxetine |
Continuous steady-state coverage once optimized |
| Cannot swallow pills |
Viloxazine (sprinkle on food) |
Capsule opens for sprinkling; atomoxetine cannot be opened |
| Comorbid SUD + depression |
Consider Bupropion (off-label, 3rd line) |
Non-controlled, dual ADHD + depression utility. Also FDA-approved for smoking cessation (as Zyban). Dopaminergic activity may help with nicotine cravings and anhedonia/craving associated with substance withdrawal |
| CYP2D6 poor metabolizer or on fluoxetine/paroxetine |
Viloxazine (over atomoxetine) |
Not a CYP2D6 substrate, no pharmacogenomic dosing complications |
Combination Strategy Evidence Summary
| Combination |
Evidence Level |
Key Finding |
Primary Indication |
| Stimulant + Alpha-2 agonist |
Strong (RCTs, meta-analysis) |
Additional SMD −0.36; 15% stimulant-sparing effect (Hirota 2014; Kollins 2011) |
Residual impulsivity, emotional dysregulation, rebound, insomnia, tics |
| Stimulant + Atomoxetine |
Moderate (retrospective, open-label) |
Meaningful improvement in treatment-resistant cases; 24-hr bridge coverage |
Documented failure of sequential monotherapy trials only |
| MPH + SSRI |
Strong safety data (N=17,234) |
No increased severe adverse events; reduced headache risk (Lee 2024) |
Comorbid depression/anxiety. MPH preferred over AMP (CYP2D6 safe) |
| AMP + SSRI |
Use with caution |
Fluoxetine/paroxetine inhibit CYP2D6, which may elevate AMP levels (though most AMP is excreted renally, so clinical significance can be modest). Theoretical serotonin syndrome risk, though clinically significant cases at therapeutic doses are rare. |
Prefer MPH + SSRI when possible. If AMP is required with an SSRI, use lower doses with slower titration and monitor closely. Avoid fluoxetine/paroxetine specifically if alternatives exist (escitalopram, sertraline are CYP2D6-neutral). Specialist supervision recommended for complex cases |
Discontinuation Protocols
| Medication |
Taper Required? |
Protocol |
Risk of Abrupt Cessation |
| Atomoxetine |
No formal taper required |
Can stop; gradual reduction preferred |
Minimal, no rebound syndrome |
| Guanfacine XR |
YES, MANDATORY |
Reduce by ≤1 mg every 3-7 days |
Rebound hypertension, tachycardia, headache, agitation; potentially dangerous |
| Clonidine XR |
YES, MANDATORY |
Reduce by ≤0.1 mg every 3-7 days |
Same as guanfacine but potentially more severe (broader receptor binding) |
| Viloxazine ER |
No formal taper required |
Gradual reduction preferred |
Minimal, serotonergic discontinuation syndrome theoretically possible |
Critical counseling point: Unlike stimulant "drug holidays," alpha-2 agonists must NEVER be skipped. Forgetting medication for 2–3 days (e.g., on vacation) can produce medically dangerous rebound effects. Educate every family at initiation.
Off-Label Third-Line Agents (Brief Reference)
| Agent |
Effect Size |
Key Niche |
Major Risk |
| Bupropion |
SMD −0.50 (Cochrane, low-quality evidence) |
Comorbid SUD + depression; dual utility from single agent |
Seizure risk (dose-dependent, 0.1–0.4%); contraindicated in seizure/eating disorders |
| Modafinil |
Variable; no QoL benefit in modern meta-analyses |
Diminishing evidence; SJS risk led to FDA pediatric rejection |
Stevens-Johnson Syndrome (~6/million person-yrs) |
| TCAs (desipramine) |
SMD -1.42 (parent); -0.97 (teacher). Caveat: based on only 6 RCTs with 216 total participants; older data with less rigorous methodology than modern trials |
Under specialist supervision only, after all other options exhausted |
Cardiac conduction abnormalities; sudden death reports in children. Baseline ECG mandatory. Narrow therapeutic index. CYP2D6 PMs at high risk of toxic accumulation |
This quick reference tool is extracted from Module 4: Non-Stimulant & Adjunct Pharmacotherapy. For full evidence review, clinical vignettes, pharmacogenomic detail, and complete references, see the full clinical module.
For the full clinical curriculum, visit psychhq.com
Key References: Cortese et al. (2018) Lancet Psychiatry; Hirota et al. (2014) JAACAP; Ostinelli et al. (2025) Lancet Psychiatry; CPIC Guideline (2019); Yu et al. (2024) JAMA Network Open; Lee et al. (2024) JAMA Network Open