Pilot Trial of SDX/d-MPH Adult ADHD Examining Effects Throughout the Day

Abstract

Objective

To examine the effects of Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) on ADHD symptoms throughout the day in adults with DSM-5 ADHD.

Method

This was a 6-week pilot study that included 3 weeks of open label treatment with SDX/d-MPH (39.2/7.8 mg/day to 52.3/10.4 mg/day in clinical titration) after completion of a one-week screening period and a two-week observation period in seventeen adults with ADHD. Two subjects were discontinued from the trial, one for being placebo-responder and another for exhibiting blood pressure lability during the observation period. Of the remaining 15 subjects, one dropped out after one week on 39.2/7.8 mg/day, while all others completed the trial. All fifteen participants were included in the data analyses.

Results

There were substantial effects of SDX/d-MPH on all clinical measures, including investigator symptom scores (AISRS); self-report (ASRS) scores, time-sensitive ADHD (TASS) scores throughout the day, impairment (CGI) and executive function scores (BRIEF-A) and measures of medication smoothness (AMSES). SDX/d-MPH was generally well tolerated.

Conclusions

This pilot study is the first systematic treatment effect trial data for SDX/d-MPH in adults with DSM-5 ADHD. The data preliminarily supports the clinical efficacy of DSM/d-MPH in adult ADHD and its ability to ameliorate symptoms throughout the day.

Introduction

Attention deficit hyperactivity disorder (ADHD) is a common developmental neuropsychiatric development disorder affecting 4.4% of the US and 3.4% of world-wide adult population.^1,2 Although surveillance studies since the COVID-19 pandemic have shown that the rates of adult ADHD diagnosis and treatment may have increased, many adults with ADHD remain undiagnosed and undertreated.³ Untreated ADHD in adults is associated with substantial costs to the individual and society at large with reported higher rates of marital discord, divorce or separation, motor vehicle accidents, substance use disorders, and lower academic and workplace achievement.^4,5 Stimulants (eg., methylphenidate or amphetamine preparations) are the most frequently used medications for adult ADHD. A recent network meta-analysis indicated that stimulants and the non-stimulant atomoxetine were the only interventions that were found to be efficacious via clinician and self-reported outcomes of core ADHD symptoms in adults.⁶ Reflecting the DSM-5 requirement that ADHD symptoms cause impairment in multiple dimensions,⁷ the treatment of adult ADHD should focus on symptomatic relief throughout the day with an agent that does not require multiple daily doses of shorter-acting stimulants, as this can worsen treatment adherence.^8,9

Methylphenidate products represent one of two classes of stimulant medications approved to treat adult ADHD. Methylphenidate preparations come in racemic, mixed forms of d/l isomers and an isolated d-isomer, which is thought to be the active form of the compound.¹⁰ Additionally, there are immediate and sustained release preparations of methylphenidate, which are used to treat adult ADHD.^6,11

Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH; Azstarys®, Corium LLC, Boston, MA, USA) is a medication that contains 30% d-MPH and 70% SDX (d-MPH prodrug) and is approved for individuals ages 6 and older with ADHD. The intent of this drug design was to provide early-onset action with the d-MPH and sustained action with the prodrug SDX, which is converted over time to d-MPH in the lower GI tract.^12–14 Efficacy in ADHD of SDX/d-MPH has been established via a placebo (PBO) controlled classroom trial in 149 children (age 6–12 years),¹³ with significant improvement in ADHD symptoms for SDX/d-MPH versus PBO from 0.5 to 13 hours after dosing.¹³ The efficacy of SDX/d-MPH in children with ADHD was further established in an open-label 12-month safety trial via dose optimization of SDX/d-MPH in 282 children with ADHD.^12,15

Although SDX/d-MPH is approved for individuals with ADHD 6 years and up, there is no published systematic data examining the effect of SDX/d-MPH in adults with ADHD. We present the results of a pilot, open-label investigation of three weeks of dose-optimized treatment with SDX/d-MPH, following a two-week observation period for rating stabilization, which we believe represents the first systematic treatment effect trial for SDX/d-MPH in adults with ADHD.

Materials and Methods

Study Design

This was a 6-week trial that examined the effects of SDX/d-MPH on adults with ADHD, specifically on symptoms of ADHD including Inattention (IA), Hyperactivity-Impulsivity (HI), Executive Functioning Deficits (EFD), and Emotion Dyscontrol (EC) throughout the day into early evening. All participants received 3 weeks of open label treatment with SDX/d-MPH after completion of a one-week screening period and a two-week observation period (OP). Participants and investigators were aware of the form of treatment and dosage. Participants who had a change in total ADHD symptom scores (total AISRS) by ⩾ 30% during the OP were considered ineligible, and did not proceed to the treatment phase. The subjects, who were deemed ineligible, were thought to have highly variable ADHD symptomatology, making it difficult to assess if changes with treatment were primarily related to medication effects (Figure 1).

Figure 1.

Consort Diagram

A total of 29 participants were screened for eligibility, and 15 participants received SDX/d-MPH. One participant was withdrawn from treatment due to adverse symptoms. The final analysis included 15 participants.

After the two-week OP, three weeks of treatment was initiated using ratings from the end of the two-week period as the new baseline ratings of the ADHD symptoms (Week 2). Participants began daily treatment with 39.2/7.8 mg dosages of SDX/d-MPH in the first week. Subsequently, the SDX/d-MPH dosage was uptitrated to 52.3/10.4 mg, based on factors such as clinical response and tolerability as assessed by the investigator. The dose of SDX/d-MPH was held constant over the last week of treatment (Week 5).

The following inclusion criteria were used: (1) were male or female between the ages of 18–60 of all races and ethnicity; (2) met DSM-5 criteria for a primary diagnosis of inattentive or combined presentation ADHD as diagnosed via Adult ADHD Clinical Diagnostic Scale (ACDS) v1.2; (3) if not receiving pharmacological treatment for ADHD, must have an AISRS 18 item total score of AISRS expanded of ⩾ 28 at screening, (4) if receiving pharmacological treatment for ADHD at screening, must have a minimum total AISRS 18 item score of ⩾ 22 at screening; (5) if there was concurrent diagnosis of dysthymia and anxiety disorders in remission, must be stable on psychiatric medication for at least three weeks and should hold constant through the trial, at the discretion of principal investigator; (6) must not have not used stimulant medication consistently in the past 2 months.

Exclusion criteria were as follows; (1) known hypersensitivity, allergy, or nonresponse to SDX/d-MPH, or product components; (2) simultaneous treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the 14 days before study participation; (3) history of lifetime bipolar disorder, psychotic disorders, autism. Intellectual disability except mood disorders accepted under the inclusion criteria at the investigator’s discretion; (4) active suicidality within the past year as determined by the Columbia-Suicide Severity Rating Scale (C-SSRS); (5) history of past or current drug dependence/substance abuse at investigator’s discretion screened through use of the Mini International Neuropsychiatric Interview 7.02 (MINI) and urine drug toxicology at baseline, with exception for marijuana use of less than three times a week and/or history of excessive marijuana use of less than three times a week within 6 months; (6) use of any prescribed benzodiazepines; and (7) any clinical issues that the investigator determined would prevent participation or compromise their safety.

The study was approved by the Institutional Review Board of New York University Grossman School of Medicine and has been registered at ClinicalTrials.gov (identifier: NCT09000501).

Assessments

Participants were assessed for DSM-5 defined adult ADHD using the expanded Adult ADHD Clinical Diagnostic Scale (ACDS) v1.2, and other current and prior DSM-5 disorders using the MINI. All raters were certified and trained using the standard procedure.¹⁶ The participants’ symptomatology of adult ADHD was ascertained using the Adult ADHD Investigator Symptom Rating Scale (AISRS) and Adult ADHD Self Report Scale (ASRS). The Time-Sensitive ADHD Symptom Scale (TASS) was used to assess adult ADHD symptoms throughout the day of assessment: first at approximately 30 to 60 minutes after dosage (TASS 1), then at around four hours post-dose (TASS 2), and finally at about 12 hours after dosing (TASS 3). The Adult ADHD Medication Smoothness of Effect Scale (AMSES), administered at the same instances as the TASS, was used to assess the consistency and duration of study medication. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was administered to assess executive function deficits and Clinical Global Impression-Severity (CGI-S) scale was used to measure impairment magnitude. The Columbia-Suicide Severity Rating Scale was used to measure suicidality. Investigators in the study performed the clinician-based assessments (ACDS v1.2, MINI, AISRS, TASS, AMSES, CGI-S, C-SSRS). Participant report scales (ASRS and BRIEF-A), participant demographics, and medical/psychiatric histories were self-reported.

The study was conducted in the outpatient setting at the NYU Grossman School of Medicine from 11/13/2023 (first consented participant) to 7/17/2024 (last participant study visit). Clinical assessments were collected both in-person and remotely with IRB approval. All safety assessments including physical examinations, electrocardiogram, vital signs monitoring, and drug accountability, were conducted in person by study personnel. All clinical assessments were administered by a board-certified clinical psychiatrist (LAA, DA, MTG). The MINI and ACDS v1.2 were used to establish ADHD and other diagnoses during screening. If eligible, the participant’s ADHD symptoms and impairment severity were assessed using the CGI-S, AISRS, and ASRS. Time sensitive ratings relating to both ADHD symptoms and medication smoothness were assessed three times a day at baseline using the TASS and AMSES respectively. Executive dysfunction was assessed using the BRIEF-A. Participant safety was monitored by assessing vital signs, adverse events, medication review, and C-SSRS. All assessments after screening were completed weekly, with the final assessment performed on the participants’ final day of study medication. The safety assessments, BRIEF-A, CGI-S, ASRS, and AISRS were administered at screening and continued weekly until the end of treatment, except at the halfway point of observational stabilization, where only the CSSRS was performed remotely. The TASS and AMSES were assessed at baseline, weekly, and at the conclusion of study treatment. All participants were informed about study details and provided written consent prior to enrollment.

Adult ADHD Clinical Diagnostic Scale (ACDS) V1.2

The Adult ADHD Clinical Diagnostic Scale (ACDS) v1.2^17,18 is a semi-structured, diagnostic interview used to diagnose adult ADHD. The ACDS v1.2 assesses for the presence of childhood symptoms of ADHD and explores recent (past year) adult symptoms with an expanded set of questions that includes all DSM-5 criteria A1 and A2 symptoms and uses stem questions and prompts. ADHD presentation and severity is decided by the clinician after covering all prompts and probes for the specific symptom. The rating is on a discrete scale ranging from 1 (never), 2 (mild), 3 (moderate), or 4 (severe), concluding with the establishment of a “yes/no” diagnosis of DSM-5 adult ADHD, along with type of presentation.^17,18

Mini 7.02

The MINI was used to screen for the presence of current and prior comorbidities. The MINI assesses DSM-5 psychiatric disorders using a clinical interview and has been widely used to evaluate psychiatric comorbidity in adult ADHD studies.¹⁹

The Adult ADHD Investigator Symptom Rating Scale (AISRS)

The AISRS is an instrument that assesses symptoms of adult ADHD, using 18 semi structured rating questions. The AISRS has been validated previously as a measure of treatment efficacy.^20,21 Clinicians can use it to probe and explore each symptom using prompts that correlate to each specific adult symptom presentation. The patient’s responses are used to rate symptoms along a 4-point scale; 0 = none, 1 = mild, 2 = moderate, or 3 = severe. These 18-items are summed to produce three scores: an inattentive (IA) subscale score (n = 9), a hyperactive-impulsive (H-I) subscale score (n = 9) and a total combined ADHD symptom score. The combined total ADHD symptom (IA and HI) score is the primary outcome measure for this trial and has been used in several previous adult ADHD treatment trials.^20–22

The Adult ADHD Self-Report Scale (ASRS)

The ASRS is an 18-item questionnaire covering the 18 symptoms of DSM-5 adult ADHD symptoms. The scale was developed by the World Health Organization (WHO) workgroup on adult ADHD. This reliable, validated self-report uses a 5-point Likert-type scale to rate symptoms by frequency (0 = never, 1 = rarely, 2 = sometimes, 3 = often, and 4 = very often). Ratings ranging from 2 to 4 are suggestive of clinical impairment. This tool provides an inventory of adult ADHD symptoms either during an initial diagnostic evaluation or when evaluating patient response to a certain treatment. The 18 items are totaled, producing three scores; an inattentive (IA) subscale score (n = 9), a hyperactive-impulsive (H-I) sub scale score (n = 9) and a total combined ADHD symptom score. The ASRS may be expanded to include an additional 13 items, which focuses upon executive function deficits (EFD; nine items) and emotional dyscontrol (ED; four items). EFDs include symptoms related to higher-level cognitive processes such as organization, planning, initiating tasks, and planning. EDs are described as behaviors of unstable mood, irritability, and emotional over-reactivity. This questionnaire has been validated for adults with ADHD, based on DSM-5 criteria, and norms are available for both the 18-item and expanded versions.^1,23–26

Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A)

The Brief-A is a 75 item self-report validated scale, which determines clinically significant levels of impairment using T-scores ⩾ 65 for indices and composite scores. The scale is comprised of three major divisions: The Metacognition Index (MI), The Behavioral Regulation Index (BRI) and The Global Executive Complex (GEC). These divisions are further composed of nine clinical subscales, all measuring behaviors associated with executive functioning. The MI division includes five subscales assessing cognitive manifestations of symptoms. The BRI division includes four subscales relating to the ability to regulate behavioral responses. The GEC is a global measuring of executive function comprising of the aforementioned nine subscales. We are reporting the T-scores for the MI, BRI, and GEC for this trial, as these are corrected for population norms.²⁷

The Clinical Global Impression Severity (CGI-S)

The CGI-S scale has been widely used to assess the overall impairment due to ADHD. This is accomplished using a 7-point Likert rating where a rating of 1 is normal and 7 is among the most severely ill patients.²⁸

Time Sensitive Adult ADHD Symptom Scale (TASS)

The TASS is an 18-item self-report scale measuring the 18 DSM-5 symptoms of ADHD. The TASS, modified from the ASRS, uses language to capture ADHD symptoms at the time of assessment. It may be repeated several times to measure the symptom fluctuations through the course of the day. The scale uses a 4-point scale (0 = not at all, 1 = mild, 2 = moderate, 3 = severe), and has a ‘not applicable’ option to indicate if a particular task or symptom has not yet been encountered. The 18 items are totaled, producing three scores; an inattentive (IA) subscale score (n = 9), a hyperactive-impulsive (H-I) subscale score (n = 9), and a total combined ADHD symptom score. The TASS has been used as a measure of treatment response^20,29 and validated against other ADHD symptom scales.³⁰ The TASS total (IA + HI) scores will be reported in this trial.

Adult ADHD Medication Smoothness of Effect Scale (AMSES)

The AMSES is a 6-item, frequency-based, self-report scale that was developed to assess the consistency and duration of effect of ADHD medication throughout the day.³⁰ The AMSES compares the effectiveness of ADHD medications over the course of the day.³¹ The AMSES contains two components: a Likert, frequency-based scale (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = very often) to elucidate the medication’s perceived impacts and to assess the smoothness of effects at a single point in time as well as a 100-mm line with anchor points related to degrees of smoothness in which the participants self-rates the overall smoothness of the medication.

Participants

Twenty-nine participants were screened for eligibility with 12 of those being excluded (see Figure 1); 17 participants were approved to receive open label treatment, with one withdrawing due to a greater than 30% decrease in ADHD symptoms as reported by AISRS prior to treatment. Another participant was withdrawn from the study due to safety concerns related to unstable blood pressure before treatment initiation. Fifteen participants were enrolled to treatment with SDX/d-MPH and 14 completed three weeks of treatment. One participant was withdrawn after one week of treatment with SDX/d-MPH 39.2/7.8 mg/day due to concerns of irritability and loss of appetite.

Sixteen participants presented with Combined type of adult ADHD and one participant presented with the Primarily Inattentive type. Ten individuals were female and seven were male. Participant ages ranged from 21 to 55 years of age (mean = 31.2 years and ± 8.9 SD). Four participants had past episodes of major depression; three patients had major depression, recurrent in remission. The other 10 participants did not have current or prior major psychiatric disorders, except for adult ADHD. Three of the participants who entered the treatment phase had previously been treated clinically with single trials of amphetamine medications, which were stopped at least three months prior to entering the trial because of non-response or intolerance; the remaining participants did not have a history of stimulant treatment prior to entering the investigation. Two of these three individuals with prior stimulant therapy went on to enter the treatment phase of this investigation. No participants had prior trials of non-stimulant ADHD medications.

Data Analyses

Treatment effects were assessed using clinical primary and secondary measures (AISRS: Total (IA + HI), IA, HI, EFD, EC; ASRS: Total (IA + HI), IA, HI, EFD, EC; BRIEF-A: GEC, BRI, MI: CGI-S; TASS Total (IA + HI)) and calculating means and standard deviations (SDs) at Baseline (Base) to End of Treatment (EoT), along with change scores, percentage change, 95% confidence intervals (CIs) and Effect Sizes (ES – Cohen’s d, with Hedges’ correction given the relatively small sample size). The last treatment visit was considered the endpoint, and any missing data was addressed using the last observation carried forward method. Similarly, changes in blood pressure and pulse were examined via means, SDs from baseline to EoT. Changes in AMSES scores, as previously described in a study of the amphetamine pro-drug lisdexamfetamine³² will be shown graphically over weeks of treatment. All analyses used R, version 4.3.1 (R Core Team, 2023) and SPSS (IBM SPSS Statistics (Version 28)).

Results

Fifteen participants entered the treatment phase with SDX/d-MPH. One participant withdrew after the first week of initial dosing and did not undergo dose titration; their data are included in the analyses. Twelve participants were treated with a SDX/d-MPH dose of 39.2/7.8 mg/day, while three participants were titrated to the higher dose of 52.3/10.4 mg/day. We included data from the baseline and final week of the treatment in the analyses (N = 15).

Significant effects of SDX/d-MPH were seen in AISRS total, AISRS IA, AISRS HI, AISRS EFD, AISRS EC, ASRS total, ASRS IA, ASRS HI, ASRS EFD, ASRS EC, CGI-S, GEC t-, MI t-, BRI t-, and early, mid and late day scores in TASS total (Table 1). The smoothness of medication effect was also observed (Figures 2 and 3). Figure 2 shows the mean AMSES scores for the global assessment of daily smoothness after each treatment week. During weeks of 3, 4, and 5 of treatment, the mean medication effect compared to 2-hour post-dose measured at 4, 6, 8, and 12-hour post-dose progressively increased, except at 10-hour post-dose (Figure 3).

Table 1. Clinical Assessments at Baseline and End of Azstarys Treatment.

		Clinical measure		Base (SD)		EoT (SD)		Change Base-EoT (SD)		% Change		95% CI [Lower, upper]		ES
N = 15		Total AISRS		36.5 (5.3)		12.4 (7.2)		24.1 (7.4)		66%		[20.0, 28.2]		3.1
		AISRS Expanded IA		20.9 (3.0)		6.6 (3.7)		14.3 (4.0)		68%		[12.1, 16.5]		3.4
		AISRS Expanded HI		15.5 (2.9)		5.8 (4.1)		9.7 (4.2)		63%		[7.4, 12.0]		2.2
		AISRS Expanded EFD		21.4 (4.2)		6.9 (5.4)		14.5 (5.1)		68%		[11.7, 17.3]		2.7
		AISRS Expanded EC		8.1 (4.6)		2.7 (3.0)		5.3 (4.8)		66%		[2.7, 8.0]		1
N = 14		ASRS Total		47.29 (9.7)		21.7 (11.3)		25.6 (13.7)		54%		[17.6, 33.5]		1.8
		ASRS IA		26.5 (4.9)		12.1 (6.2)		14.4 (7.6)		54%		[10.1, 18.8]		1.8
		ASRS HI		20.8 (5.8)		9.6 (5.6)		11.1 (7.2)		54%		[7.0, 15.3]		1.5
		ASRS EFD		23 (4.8)		10.4 (6.0)		12.6 (6.2)		55%		[9.0, 16.2]		1.9
		ASRS EC		11.8 (3.7)		5.9 (3.5)		5.9 (5.0)		50%		[3.0, 8.8]		1.1
N = 15		BRI		62.3 (9.8)		50.4 (12.4)		11.9 (12)		19%		[5.3, 18.6]		0.9
		MI		78 (7.6)		55.9 (13.2)		22.1 (15.3)		28%		[13.7, 30.6]		1.4
		GEC		73.1 (7.9)		53.9 (13.6)		19.2 (14.3)		26%		[11.3, 27.1]		1.3
N = 15		CGI-S		4.67 (0.6)		2.9 (0.7)		1.7 (1.0)		37%		[1.2, 2.3]		1.7
N = 15		TASS
		Total morning		22.3 (11.2)		10.1 (4.6)		12.3 (10)		45%		[6.7, 17.8]		1.2
		Total mid-day		21.9 (9.7)		9.3 (7.9)		12.6 (10.5)		42%		[6.8, 18.3]		1.1
		Total evening		21.2 (10.5)		11.9 (9.2)		9.3 (10.5)		56%		[3.4, 15.1]		0.8

Base = Baseline; EoT = End of Treatment, SD = Standard Deviation; CI = Confidence Interval; ES = Effect Size.

Figure 2.

Global Smoothness of Daily Medication Effect

The global assessment of daily smoothness over the course of treatment is shown in the figure.

Figure 3.

Mean AMSES Scores at 4, 6, 8, 10, and 12 HR Post-Dose as Compared with 2 HR Post-Dose

The mean AMSES scores for each time point after treatment weeks following 4-, 6-, 8-, 10-, and 12-hour are shown in the above figure.

Safety

Overall, SDX/d-MPH was well tolerated by trial participants; no serious adverse events were reported. Adverse events reported during the study ranged from mild to moderate with the majority being mild and none led to discontinuing a participant from the trial. The most commonly reported adverse events were headache (24%), nausea (16%), insomnia (11%), tachycardia (11%), anxiety (11%) and dyspepsia (8%). However, these adverse events are commonly reported with stimulants in general and are not clearly specific to SDX/d-MPH. There were no reports of suicidality or suicidal ideation from participants during the study. The changes to systolic and diastolic blood pressure (BP) (mmHg) and pulse (beats/ min-bpm) with SDX/d-MPH treatment were minor and clinically insignificant. The mean systolic BP was 109.9 (9.7) (SD) mmHg at start of treatment and 118.8 (10.0) mmHg at end of treatment, reflecting a 8.9 mmHg change from baseline to the end of treatment. The mean diastolic BP was 71.1 (7.3) (SD) mmHg at start and 75.5 (7.8) mmHg at end, reflecting 4.4 mmHg change. The pulse was 81.5 (12.8) (SD) bpm at start and 90 (14.4) bpm at end, showing a 8.5 bpm difference.

Discussion and Conclusions

To our knowledge, this pilot study is the first systematic clinical treatment effect trial data for SDX/d-MPH in adults with ADHD, which supports its clinical efficacy. The change observed on the primary outcome measure, the total ADHD symptom score on the AISRS, was somewhat larger than score changes seen in other stimulant trials; the larger magnitude effect size might have been due to the small sample size and absence of placebo control in this pilot trial. Substantial improvement was also seen on clinician ratings of inattention, hyperactivity-impulsivity, executive function deficits, and emotional dysregulation on the AISRS with comparable effects noted on overall and subset measures on participant ADHD scores as the ASRS. The overall improvement in patient-reported executive functioning on the BRIEF-A was relatively similar in magnitude to that observed in prior stimulant trials in adult ADHD. Improvement on clinician ratings of impairment via the CGI-I were also noted. The two participants who had previous treatment with stimulants prior to the trial had responses similar to the cohort who did not have prior stimulant exposure as adults. Of note and as observed previously, stimulant effects on executive function deficits and emotional dysregulation may be less than that which is seen on core ADHD symptoms. It should also be noted that these relatively large effects on ADHD symptoms were observed with only 20% of the participants needing titration to the higher dose of 52.3/10.4 mg/day of SDX/d-MPH and that 80% were treated with the 39.2/7.8 mg/day dose, which is the middle of the clinically available doses of this compound; whether this titration pattern would persist in larger studies with more varied participant samples is not known.

Time-sensitive effects were observed in the morning, mid-day and into the evening across treatment weeks throughout the trial, supporting the concept that SDX/d-MPH may offer treatment effects throughout the day. One potential concern with ADHD medications which have sustained effects throughout the day is the potential for influencing sleep. Insomnia in this trial was reported as an adverse event at a rate (11%), which is somewhat less than the adverse event insomnia rate observed in the open label trial of d-MPH XR in adults (six months – 20%)³³ and somewhat greater than the rate seen in the SDX/d-MPH open trial in children (twelve months - circa 5%).¹⁵ Medication smoothness overall (assessed via 100-mm line assessment with anchor points) was quite high and similar to that which was observed in a trial of an amphetamine pro-drug, lisdexamfetamine.³² Smoothness measures comparing effects at time points throughout the day versus the two-hour post dose measure indicated observed drug smoothness. As expected, smoothness measures worsened at assessment times late in the day (10 and 12 hours post dose) when compared to earlier in the day. However, measures of drug smoothness also seemed to improve with sustained treatment through the duration of the trial.

Adverse events noted during this trial with SDX/d-MPH were similar to those seen with stimulants overall and consistent with adverse effects observed in other trials with SDX/d-MPH. The changes in blood pressure and heart rate were in the same range as in prior stimulant trials and did not lead to tolerability issues or participant discontinuation from our study.

These results must be viewed with some caution because of the absence of having a true placebo control, the short treatment epoch (three weeks), and relatively small sample size. The lack of a placebo control was in part mitigated by employing an observation rating period of two weeks to control participant expectation bias and stabilize ratings.

This study supports the efficacy of SDX/d-MPH in adults with ADHD and provides insights about its effects on executive function deficits and emotional control, which are features relevant to the clinical phenotype of adult ADHD. Future studies should focus on more controlled investigations with placebo controls and larger samples. Also, future studies allowing for longer treatment epochs would allow for close examination of medication smoothness and treatment efficacy at late times in the day.

In conclusion, this trial observed treatment effects of SDX/d-MPH throughout the day and extending well into the late-day, thereby supporting its efficacy as a once daily medication for adults with ADHD.