Melody Grace Santos, MD

SECOND OF 2 PARTS

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional impairment.¹ ADHD begins in childhood, continues into adulthood, and has negative consequences in many facets of adult patients’ lives, including their careers, daily functioning, and interpersonal relationships.² According to the National Institute of Health and Care Excellence’s recommendations, both pharmacotherapy and psychotherapy are advised for patients with ADHD.³ Although various pharmacotherapies are advised as first-line treatments for ADHD, they are frequently linked to unfavorable adverse effects, partial responses, chronic residual symptoms, high dropout rates, and issues with addiction.⁴ As a result, there is a need for evidence-based nonpharmacologic therapies.

In a systematic review, Nimmo-Smith et al⁵ found that certain nonpharmacologic treatments can be effective in helping patients with ADHD manage their illness. In clinical and cognitive assessments of ADHD, a recent meta-analysis found that noninvasive brain stimulation had a small but significant effect.⁶ Some evidence suggests that in addition to noninvasive brain stimulation, other nonpharmacologic interventions, including psychoeducation (PE), mindfulness, cognitive-behavioral therapy (CBT), and chronotherapy, can be effective as an adjunct treatment to pharmacotherapy, and possibly as monotherapy.

Part 1 of this 2-part article reviewed 6 randomized controlled trials (RCTs) of pharmacologic interventions for adult ADHD published within the last 5 years.⁷ Part 2 analyzes 6 RCTs of nonpharmacologic treatments for adult ADHD published within the last 5 years (Table^8-13).

1. Leffa DT, Grevet EH, Bau CHD, et al. Transcranial direct current stimulation vs sham for the treatment of inattention in adults with attention-deficit/hyperactivity disorder: the TUNED randomized clinical trial. JAMA Psychiatry. 2022;79(9):847-856. doi:10.1001/jamapsychiatry.2022.2055

Transcranial direct current stimulation (tDCS) uses noninvasive, low-intensity electrical current on the scalp to affect underlying cortical activity.¹⁴ This form of neurostimulation offers an alternative treatment option for when medications fail or are not tolerated, and can be used at home without the direct involvement of a clinician.¹⁴ tDCS as a treatment for ADHD has been increasingly researched, though many studies have been limited by short treatment periods and varied methodological approaches. In a meta-analysis, Westwood et al⁶ found a trend toward improvement on the function of processing speed but not on attention. Leffa et al⁸ examined the efficacy and safety of a 4-week course of home-based tDCS in adult patients with ADHD, specifically looking at reduction in inattention symptoms.

Study design

• This randomized, double-blind, parallel, sham-controlled clinical trial evaluated 64 participants age 18 to 60 from a single center in Brazil who met DSM-5 criteria for combined or primarily inattentive ADHD.
• Inclusion criteria included an inattention score ≥21 on the clinician-administered Adult ADHD Self-report Scale version 1.1 (CASRS). This scale assesses both inattentive symptoms (CASRS-I) and hyperactive-impulsive symptoms (CASRS-HI). Participants were not being treated with stimulants or agreed to undergo a 30-day washout of stimulants prior to the study.
• Exclusion criteria included current moderate to severe depression (Beck Depression Inventory-II [BDI] score >21), current moderate to severe anxiety (Beck Anxiety Inventory [BAI] score ≥21), diagnosis of bipolar disorder (BD) with either a manic or depressive episode in the year prior to study, diagnosis of a psychotic disorder, diagnosis of autism spectrum disorder (ASD), positive screen for substance use, unstable medical condition resulting in poor functionality, pregnant or planning on becoming pregnant within 3 months of the study, not able to use home-based equipment, history of neurosurgery, presence of ferromagnetic metal in the head or presence of implanted medical devices in head/neck region, or history of epilepsy with reported seizures in the year prior to the study.
• Participants were randomized to self-administer real or sham tDCS; the devices looked the same. Participants underwent daily 30-minute sessions using a 2-mA direct constant current for a total of 28 sessions. Sham treatment involved a 30-second ramp-up to 2-mA and a 30-second ramp-down sensation at the beginning, middle, and end of each respective session.
• The primary outcome was a change in symptoms of inattention per CASRS-I. Secondary outcomes were scores on the CASRS-HI, BDI, BAI, and Behavior Rating Inventory of Executive Functions-Adult (BRIEF-A), which evaluates executive function.

Outcomes

• A total of 53 participants used stimulant medications prior to the study and 8 required a washout. The average age was 38.3, and 53% of participants were male.
• For the 55 participants who completed 4 weeks of treatment, the mean number of sessions was 25.2 in the tDCS group and 24.8 in the sham group.
• At the end of Week 4, there was a statistically significant treatment by time interaction in CASRS-I scores in the tDCS group compared to the sham group (18.88 vs 23.63 on final CASRS-I scores; P < .001).
• There were no statistically significant differences in any of the secondary outcomes.

Conclusions/limitations

• This study showed the benefits of 4 weeks of home-based tDCS for managing inattentive symptoms in adults with ADHD. The authors noted that extended treatment of tDCS may incur greater benefit, as this study used a longer treatment course compared to others that have used a shorter duration of treatment (ie, days instead of weeks). Additionally, this study placed the anodal electrode over the right dorsolateral prefrontal cortex (DLPFC) vs over the left DLPFC, because there may be a decrease in activation in the right DLPFC in adults with ADHD undergoing attention tasks.¹⁵
• This study also showed that home-based tDCS can be an easier and more accessible way for patients to receive treatment, as opposed to needing to visit a health care facility.
• Limitations: The dropout rate (although only 2 of 7 participants who dropped out of the active group withdrew due to adverse events), lack of remote monitoring of patients, and restrictive inclusion criteria limit the generalizability of these findings. Additionally, 3 patients in the tDCS group and 7 in the sham group were taking psychotropic medications for anxiety or depression.

Continue to: #2

 

 

2. Hoxhaj E, Sadohara C, Borel P, et al. Mindfulness vs psychoeducation in adult ADHD: a randomized controlled trial. Eur Arch Psychiatry Clin Neurosci. 2018;268(4):321-335. doi:10.1007/s00406-018-0868-4

Previous research has shown that using mindfulness-based approaches can improve ADHD symptoms.^16,17 Hoxhaj et al⁹ looked at the effectiveness of mindfulness awareness practices (MAP) for alleviating ADHD symptoms.

Study design

• This RCT enrolled 81 adults from a German medical center who met DSM-IV criteria for ADHD, were not taking any ADHD medications, and had not undergone any psychotherapeutic treatments in the last 3 months. Participants were randomized to receive MAP (n = 41) or PE (n = 40).
• Exclusion criteria included having a previous diagnosis of schizophrenia, BD I, active substance dependence, ASD, suicidality, self-injurious behavior, or neurologic disorders.
• The MAP group underwent 8 weekly 2.5-hour sessions, plus homework involving meditation and other exercises. The PE group was given information regarding ADHD and management options, including organization and stress management skills.
• Patients were assessed 2 weeks before treatment (T1), at the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• The primary outcome was the change in the blind-observer rated Conner’s Adult ADHD Rating Scales (CAARS) inattention/memory scales from T1 to T2.
• Secondary outcomes included the other CAARS subscales, the Brief Symptom Inventory (BSI), the BDI, the 36-item Short Form Health Survey, and the Five Facet Mindfulness Questionnaire (FFMQ).

Outcomes

• Baseline demographics did not differ between groups other than the MAP group having a significantly higher IQ than the PE group. However, this difference resolved after the final sample was analyzed, as there were 2 dropouts and 7 participants lost to follow-up in the MAP group and 4 dropouts and 4 participants lost to follow-up in the PE group.
• There was no significant difference between the groups in the primary outcome of observer-rated CAARS inattention/memory subscale scores, or other ADHD symptoms per the CAARS.
• However, there was a significant difference within each group on all ADHD subscales of the observer-rated CAARS at T2. Persistent, significant differences were noted for the observer-rated CAARS subscales of self-concept and DSM-IV Inattentive Symptoms, and all CAARS self-report scales to T3.
• Compared to the PE group, there was a significantly larger improvement in the MAP group on scores of the mindfulness parameters of observation and nonreactivity to inner experience.
• There were significant improvements regarding depression per the BDI and global severity per the BSI in both treatment groups, with no differences between the groups.
• At T3, in the MAP group, 3 patients received methylphenidate, 1 received atomoxetine, and 1 received antidepressant medication. In the PE group, 2 patients took methylphenidate, and 2 participants took antidepressants.
• There was a significant difference regarding sex and response, with men experiencing less overall improvement than women.

Conclusions/limitations

• MAP was not superior to PE in terms of changes on CAARS scores, although within each group, both therapies showed improvement over time.
• While there may be gender-specific differences in processing information and coping strategies, future research should examine the differences between men and women with different therapeutic approaches.
• Limitations: This study did not employ a true placebo but instead had 2 active arms. Generalizability is limited due to a lack of certain comorbidities and use of medications.

Continue to: #3

 

 

3. Janssen L, Kan CC, Carpentier PJ, et al. Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial. Psychol Med. 2019;49(1):55-65. doi:10.1017/S0033291718000429

Mindfulness-based cognitive therapy (MBCT) is a form of psychotherapy that combines mindfulness with the principles of CBT. Hepark et al¹⁸ found benefits of MBCT for reducing ADHD symptoms. In a larger, multicenter, single-blind RCT, Janssen et al¹⁰ reviewed the efficacy of MBCT compared to treatment as usual (TAU).

Study design

• A total of 120 participants age ≥18 who met DSM-IV criteria for ADHD were recruited from Dutch clinics and advertisements and randomized to receive MBCT plus TAU (n = 60) or TAU alone (n = 60). There were no significant demographic differences between groups at baseline.
• Exclusion criteria included active depression with psychosis or suicidality, active manic episode, tic disorder with vocal tics, ASD, learning or other cognitive impairments, borderline or antisocial personality disorder, substance dependence, or previous participation in MBCT or other mindfulness-based interventions. Participants also had to be able to complete the questionnaires in Dutch.
• Blinded evaluations were conducted at baseline (T0), at the completion of therapy (T1), 3 months after the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• MBCT included 8 weekly, 2.5-hour sessions and a 6-hour silent session between the sixth and seventh sessions. Patients participated in various meditation techniques with the addition of PE, CBT, and group discussions. They were also instructed to practice guided exercises 6 days/week, for approximately 30 minutes/day.
• The primary outcome was change in ADHD symptoms as assessed by the investigator-rated CAARS (CAARS-INV) at T1.
• Secondary outcomes included change in scores on the CAARS: Screening Version (CAARS-S:SV), BRIEF-A, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF), Self-Compassion Scale-Short Form (SCS-SF), Mental Health Continuum-Short Form (MHC-SF), and Outcome Questionnaire (OQ 45.2).

Outcomes

• In the MBCT group, participants who dropped out (n = 9) were less likely to be using ADHD medication at baseline than those who completed the study.
• At T1, the MBCT plus TAU group had significantly less ADHD symptoms on CAARS-INV compared to TAU (d = 0.41, P = .004), with more participants in the MBCT plus TAU group experiencing a symptom reduction ≥30% (24% vs 7%, P = .001) and remission (P = .039).
• The MBCT plus TAU group also had a significant reduction in scores on CAARS-S:SV as well as significant improvement on self-compassion per SCS-SF, mindfulness skills per FFMQ-SF, and positive mental health per MHC-SF, but not on executive functioning per BRIEF-A or general functioning per OQ 45.2.
• Over 6-month follow-up, there continued to be significant improvement in CAARS-INV, CAARS-S:SV, mindfulness skills, self-compassion, and positive mental health in the MBCT plus TAU group compared to TAU. The difference in executive functioning (BRIEF-A) also became significant over time.

Conclusions/limitations

• MBCT plus TAU appears to be effective for reducing ADHD symptoms, both from a clinician-rated and self-reported perspective, with improvements lasting up to 6 months.
• There were also improvements in mindfulness, self-compassion, and positive mental health posttreatment in the MBCT plus TAU group, with improvement in executive functioning seen over the follow-up periods.
• Limitations: The sample was drawn solely from a Dutch population and did not assess the success of blinding.

Continue to: #4

 

 

4. Selaskowski B, Steffens M, Schulze M, et al. Smartphone-assisted psychoeducation in adult attention-deficit/hyperactivity disorder: a randomized controlled trial. Psychiatry Res. 2022;317:114802. doi:10.1016/j.psychres.2022.114802

Managing adult ADHD can include PE, but few studies have reviewed the effectiveness of formal clinical PE. PE is “systemic, didactic-psychotherapeutic interventions, which are adequate for informing patients and their relatives about the illness and its treatment, facilitating both an understanding and personally responsible handling of the illness and supporting those afflicted in coping with the disorder.”¹⁹ Selaskowski et al¹¹ investigated the feasibility of using smartphone-assisted PE (SAP) for adults diagnosed with ADHD.

Study design

• Participants were 60 adults age 18 to 65 who met DSM-5 diagnostic criteria for ADHD. They were required to have a working comprehension of the German language and access to an Android-powered smartphone.
• Exclusion criteria included a diagnosis of schizophrenia or other psychotic disorder, antisocial personality disorder, substance use disorder, severe affective disorder, severe neurologic disorder, or initial use or dose change of ADHD medications 2 weeks prior to baseline.
• Participants were randomized to SAP (n = 30) or brochure-assisted PE (BAP) (n = 30). The demographics at baseline were mostly balanced between the groups except for substance abuse (5 in the SAP group vs 0 in the BAP group; P = .022).
• The primary outcome was severity of total ADHD symptoms, which was assessed by blinded evaluations conducted at baseline (T0) and after 8 weekly PE sessions (T1).
• Secondary outcomes included dropout rates, improvement in depressive symptoms as measured by the German BDI-II, improvement in functional impairment as measured by the Weiss Functional Impairment Scale (WFIRS), homework performed, attendance, and obtained PE knowledge.
• Both groups attended 8 weekly 1-hour PE group sessions led by 2 therapists and comprised of 10 participants.

Outcomes

• Only 43 of the 60 initial participants completed the study; 24 in the SAP group and 19 in the BAP group.
• The SAP group experienced a significant symptom improvement of 33.4% from T0 to T1 compared to the BAP group, which experienced a symptom improvement of 17.3% (P = .019).
• ADHD core symptoms considerably decreased in both groups. There was no significant difference between groups (P = .74).
• SAP dramatically improved inattention (P = .019), improved impulsivity (P = .03), and increased completed homework (P < .001), compared to the BAP group.
• There was no significant difference in correctly answered quiz questions or in BDI-II or WFIRS scores.

Conclusions/limitations

• Both SAP and BAP appear to be effective methods for PE, but patients who participated in SAP showed greater improvements than those who participated in BAP.
• Limitations: This study lacked a control intervention that was substantially different from SAP and lacked follow-up. The sample was a mostly German population, participants were required to have smartphone access beforehand, and substance abuse was more common in the SAP group.

Continue to: #5

 

 

5. Pan MR, Huang F, Zhao MJ, et al. A comparison of efficacy between cognitive behavioral therapy (CBT) and CBT combined with medication in adults with attention-deficit/hyperactivity disorder (ADHD). Psychiatry Res. 2019;279:23-33. doi:10.1016/j.psychres.2019.06.040

CBT has demonstrated long-term benefit for the core symptoms of ADHD, comorbid symptoms (anxiety and depression), and social functioning. For ADHD, pharmacotherapies have a bottom-up effect where they increase neurotransmitter concentration, leading to an effect in the prefrontal lobe, whereas psychotherapies affect behavior-related brain activity in the prefrontal lobes, leading to the release of neurotransmitters. Pan et al¹² compared the benefits of CBT plus medication (CBT + M) to CBT alone on core ADHD symptoms, social functioning, and comorbid symptoms.

Study design

• The sample consisted of 124 participants age >18 who had received a diagnosis of adult ADHD according to DSM-IV via Conner’s Adult ADHD Diagnostic Interview and were either outpatients at Peking University Sixth Hospital or participants in a previous RCT (Huang et al²⁰).
• Exclusion criteria included organic mental disorders, high suicide risk in those with major depressive disorder, acute BD episode requiring medication or severe panic disorder or psychotic disorder requiring medication, pervasive developmental disorder, previous or current involvement in other psychological therapies, IQ <90, unstable physical conditions requiring medical treatment, attending <7 CBT sessions, or having serious adverse effects from medication.
• Participants received CBT + M (n = 57) or CBT alone (n = 67); 40 (70.18%) participants in the CBT + M group received methylphenidate hydrochloride controlled-release tablets (average dose 27.45 ± 9.97 mg) and 17 (29.82%) received atomoxetine hydrochloride (average dose 46.35 ± 20.09 mg). There were no significant demographic differences between groups.
• CBT consisted of 12 weekly 2-hour sessions (8 to 12 participants in each group) that were led by 2 trained psychiatrist therapists and focused on behavioral and cognitive strategies.
• Participants in the CBT alone group were drug-naïve and those in CBT + M group were stable on medications.
• The primary outcome was change in ADHD Rating Scale (ADHD-RS) score from baseline to Week 12.
• Secondary outcomes included Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Self-Esteem Scale (SES), executive functioning (BRIEF-A), and quality of life (World Health Organization Quality of Life-Brief version [WHOQOL-BREF]).

Outcomes

• ADHD-RS total, impulsiveness-hyperactivity subscale, and inattention subscale scores significantly improved in both groups (P < .01). The improvements were greater in the CBT + M group compared to the CBT-only group, but the differences were not statistically significant.
• There was no significant difference between groups in remission rate (P < .689).
• There was a significant improvement in SAS, SES, and SDS scores in both groups (P < .01).
• In terms of the WHOQOL-BREF, the CBT + M group experienced improvements only in the psychological and environmental domains, while the CBT-only group significantly improved across the board. The CBT-only group experienced greater improvement in the physical domain (P < .01).
• Both groups displayed considerable improvements in the Metacognition Index and Global Executive Composite for BRIEF-A. The shift, self-monitor, initiate, working memory, plan/organize, task monitor, and material organization skills significantly improved in the CBT + M group. The only areas where the CBT group significantly improved were initiate, material organization, and working memory. No significant differences in BRIEF-A effectiveness were discovered.

Conclusions/limitations

• CBT is an effective treatment for improving core ADHD symptoms.
• This study was unable to establish that CBT alone was preferable to CBT + M, particularly in terms of core symptoms, emotional symptoms, or self-esteem.
• CBT + M could lead to a greater improvement in executive function than CBT alone.
• Limitations: This study used previous databases rather than RCTs. There was no placebo in the CBT-only group. The findings may not be generalizable because participants had high education levels and IQ. The study lacked follow-up after 12 weeks.

Continue to: #6

 

 

6. van Andel E, Bijlenga D, Vogel SWN, et al. Effects of chronotherapy on circadian rhythm and ADHD symptoms in adults with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome: a randomized clinical trial. Chronobiol Int. 2021;38(2):260-269. doi:10.1080/07420528.2020.1835943

Most individuals with ADHD have a delayed circadian rhythm.²¹ Delayed sleep phase syndrome (DSPS) is diagnosed when a persistently delayed circadian rhythm is not brought on by other diseases or medications. ADHD symptoms and circadian rhythm may both benefit from DSPS treatment. A 3-armed randomized clinical parallel-group trial by van Andel et al¹³ investigated the effects of chronotherapy on ADHD symptoms and circadian rhythm.

Study design

• Participants were Dutch-speaking individuals age 18 to 55 who were diagnosed with ADHD and DSPS. They were randomized to receive melatonin 0.5 mg/d (n = 17), placebo (n = 17), or melatonin 0.5 mg/d plus 30 minutes of timed morning bright light therapy (BLT) (n = 15) daily for 3 weeks. There were no significant differences in baseline characteristics between groups except that the melatonin plus BLT group had higher use of oral contraceptives (P = .007).
• This study was completed in the Netherlands with participants from an outpatient adult ADHD clinic.
• Exclusion criteria included epilepsy, psychotic disorders, anxiety or depression requiring acute treatment, alcohol intake >15 units/week in women or >21 units/week in men, ADHD medications, medications affecting sleep, use of drugs, mental retardation, amnestic disorder, dementia, cognitive dysfunction, crossed >2 time zones in the 2 weeks prior to the study, shift work within the previous month, having children disturbing sleep, glaucoma, retinopathy, having BLT within the previous month, pregnancy, lactation, or trying to conceive.
• The study consisted of 3-armed placebo-controlled parallel groups in which 2 were double-blind (melatonin group and placebo group).
• During the first week of treatment, medication was taken 3 hours before dim-light melatonin onset (DLMO) and later advanced to 4 and 5 hours in Week 2 and Week 3, respectively. BLT was used at 20 cm from the eyes for 30 minutes every morning between 7 am and 8 am.
• The primary outcome was DLMO in which radioimmunoassay was used to determine melatonin concentrations. DLMO was used as a marker for internal circadian rhythm.
• The secondary outcome was ADHD symptoms using the Dutch version of the ADHD Rating Scale-IV.
• Evaluations were conducted at baseline (T0), the conclusion of treatment (T1), and 2 weeks after the end of treatment (T2).

Outcomes

• Out of 51 participants, 2 dropped out of the melatonin plus BLT group before baseline, and 3 dropped out of the placebo group before T1.
• At baseline, the average DLMO was 11:43 pm ± 1 hour and 46 minutes, with 77% of participants experiencing DLMO after 11 pm. Melatonin advanced DLMO by 1 hour and 28 minutes (P = .001) and melatonin plus BLT had an advance of 1 hour and 58 minutes (P < .001). DLMO was unaffected by placebo.
• The melatonin group experienced a 14% reduction in ADHD symptoms (P = .038); the placebo and melatonin plus BLT groups did not experience a reduction.
• DLMO and ADHD symptoms returned to baseline 2 weeks after therapy ended.

Conclusions/limitations

• In patients with DSPS and ADHD, low-dose melatonin can improve internal circadian rhythm and decrease ADHD symptoms.
• Melatonin plus BLT was not effective in improving ADHD symptoms or advancing DLMO.
• Limitations: This study used self-reported measures for ADHD symptoms. The generalizability of the findings is limited because the exclusion criteria led to minimal comorbidity. The sample was comprised of a mostly Dutch population.

SECOND OF 2 PARTS

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional impairment.¹ ADHD begins in childhood, continues into adulthood, and has negative consequences in many facets of adult patients’ lives, including their careers, daily functioning, and interpersonal relationships.² According to the National Institute of Health and Care Excellence’s recommendations, both pharmacotherapy and psychotherapy are advised for patients with ADHD.³ Although various pharmacotherapies are advised as first-line treatments for ADHD, they are frequently linked to unfavorable adverse effects, partial responses, chronic residual symptoms, high dropout rates, and issues with addiction.⁴ As a result, there is a need for evidence-based nonpharmacologic therapies.

In a systematic review, Nimmo-Smith et al⁵ found that certain nonpharmacologic treatments can be effective in helping patients with ADHD manage their illness. In clinical and cognitive assessments of ADHD, a recent meta-analysis found that noninvasive brain stimulation had a small but significant effect.⁶ Some evidence suggests that in addition to noninvasive brain stimulation, other nonpharmacologic interventions, including psychoeducation (PE), mindfulness, cognitive-behavioral therapy (CBT), and chronotherapy, can be effective as an adjunct treatment to pharmacotherapy, and possibly as monotherapy.

Part 1 of this 2-part article reviewed 6 randomized controlled trials (RCTs) of pharmacologic interventions for adult ADHD published within the last 5 years.⁷ Part 2 analyzes 6 RCTs of nonpharmacologic treatments for adult ADHD published within the last 5 years (Table^8-13).

1. Leffa DT, Grevet EH, Bau CHD, et al. Transcranial direct current stimulation vs sham for the treatment of inattention in adults with attention-deficit/hyperactivity disorder: the TUNED randomized clinical trial. JAMA Psychiatry. 2022;79(9):847-856. doi:10.1001/jamapsychiatry.2022.2055

Transcranial direct current stimulation (tDCS) uses noninvasive, low-intensity electrical current on the scalp to affect underlying cortical activity.¹⁴ This form of neurostimulation offers an alternative treatment option for when medications fail or are not tolerated, and can be used at home without the direct involvement of a clinician.¹⁴ tDCS as a treatment for ADHD has been increasingly researched, though many studies have been limited by short treatment periods and varied methodological approaches. In a meta-analysis, Westwood et al⁶ found a trend toward improvement on the function of processing speed but not on attention. Leffa et al⁸ examined the efficacy and safety of a 4-week course of home-based tDCS in adult patients with ADHD, specifically looking at reduction in inattention symptoms.

Study design

• This randomized, double-blind, parallel, sham-controlled clinical trial evaluated 64 participants age 18 to 60 from a single center in Brazil who met DSM-5 criteria for combined or primarily inattentive ADHD.
• Inclusion criteria included an inattention score ≥21 on the clinician-administered Adult ADHD Self-report Scale version 1.1 (CASRS). This scale assesses both inattentive symptoms (CASRS-I) and hyperactive-impulsive symptoms (CASRS-HI). Participants were not being treated with stimulants or agreed to undergo a 30-day washout of stimulants prior to the study.
• Exclusion criteria included current moderate to severe depression (Beck Depression Inventory-II [BDI] score >21), current moderate to severe anxiety (Beck Anxiety Inventory [BAI] score ≥21), diagnosis of bipolar disorder (BD) with either a manic or depressive episode in the year prior to study, diagnosis of a psychotic disorder, diagnosis of autism spectrum disorder (ASD), positive screen for substance use, unstable medical condition resulting in poor functionality, pregnant or planning on becoming pregnant within 3 months of the study, not able to use home-based equipment, history of neurosurgery, presence of ferromagnetic metal in the head or presence of implanted medical devices in head/neck region, or history of epilepsy with reported seizures in the year prior to the study.
• Participants were randomized to self-administer real or sham tDCS; the devices looked the same. Participants underwent daily 30-minute sessions using a 2-mA direct constant current for a total of 28 sessions. Sham treatment involved a 30-second ramp-up to 2-mA and a 30-second ramp-down sensation at the beginning, middle, and end of each respective session.
• The primary outcome was a change in symptoms of inattention per CASRS-I. Secondary outcomes were scores on the CASRS-HI, BDI, BAI, and Behavior Rating Inventory of Executive Functions-Adult (BRIEF-A), which evaluates executive function.

Outcomes

• A total of 53 participants used stimulant medications prior to the study and 8 required a washout. The average age was 38.3, and 53% of participants were male.
• For the 55 participants who completed 4 weeks of treatment, the mean number of sessions was 25.2 in the tDCS group and 24.8 in the sham group.
• At the end of Week 4, there was a statistically significant treatment by time interaction in CASRS-I scores in the tDCS group compared to the sham group (18.88 vs 23.63 on final CASRS-I scores; P < .001).
• There were no statistically significant differences in any of the secondary outcomes.

Conclusions/limitations

• This study showed the benefits of 4 weeks of home-based tDCS for managing inattentive symptoms in adults with ADHD. The authors noted that extended treatment of tDCS may incur greater benefit, as this study used a longer treatment course compared to others that have used a shorter duration of treatment (ie, days instead of weeks). Additionally, this study placed the anodal electrode over the right dorsolateral prefrontal cortex (DLPFC) vs over the left DLPFC, because there may be a decrease in activation in the right DLPFC in adults with ADHD undergoing attention tasks.¹⁵
• This study also showed that home-based tDCS can be an easier and more accessible way for patients to receive treatment, as opposed to needing to visit a health care facility.
• Limitations: The dropout rate (although only 2 of 7 participants who dropped out of the active group withdrew due to adverse events), lack of remote monitoring of patients, and restrictive inclusion criteria limit the generalizability of these findings. Additionally, 3 patients in the tDCS group and 7 in the sham group were taking psychotropic medications for anxiety or depression.

Continue to: #2

 

 

2. Hoxhaj E, Sadohara C, Borel P, et al. Mindfulness vs psychoeducation in adult ADHD: a randomized controlled trial. Eur Arch Psychiatry Clin Neurosci. 2018;268(4):321-335. doi:10.1007/s00406-018-0868-4

Previous research has shown that using mindfulness-based approaches can improve ADHD symptoms.^16,17 Hoxhaj et al⁹ looked at the effectiveness of mindfulness awareness practices (MAP) for alleviating ADHD symptoms.

Study design

• This RCT enrolled 81 adults from a German medical center who met DSM-IV criteria for ADHD, were not taking any ADHD medications, and had not undergone any psychotherapeutic treatments in the last 3 months. Participants were randomized to receive MAP (n = 41) or PE (n = 40).
• Exclusion criteria included having a previous diagnosis of schizophrenia, BD I, active substance dependence, ASD, suicidality, self-injurious behavior, or neurologic disorders.
• The MAP group underwent 8 weekly 2.5-hour sessions, plus homework involving meditation and other exercises. The PE group was given information regarding ADHD and management options, including organization and stress management skills.
• Patients were assessed 2 weeks before treatment (T1), at the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• The primary outcome was the change in the blind-observer rated Conner’s Adult ADHD Rating Scales (CAARS) inattention/memory scales from T1 to T2.
• Secondary outcomes included the other CAARS subscales, the Brief Symptom Inventory (BSI), the BDI, the 36-item Short Form Health Survey, and the Five Facet Mindfulness Questionnaire (FFMQ).

Outcomes

• Baseline demographics did not differ between groups other than the MAP group having a significantly higher IQ than the PE group. However, this difference resolved after the final sample was analyzed, as there were 2 dropouts and 7 participants lost to follow-up in the MAP group and 4 dropouts and 4 participants lost to follow-up in the PE group.
• There was no significant difference between the groups in the primary outcome of observer-rated CAARS inattention/memory subscale scores, or other ADHD symptoms per the CAARS.
• However, there was a significant difference within each group on all ADHD subscales of the observer-rated CAARS at T2. Persistent, significant differences were noted for the observer-rated CAARS subscales of self-concept and DSM-IV Inattentive Symptoms, and all CAARS self-report scales to T3.
• Compared to the PE group, there was a significantly larger improvement in the MAP group on scores of the mindfulness parameters of observation and nonreactivity to inner experience.
• There were significant improvements regarding depression per the BDI and global severity per the BSI in both treatment groups, with no differences between the groups.
• At T3, in the MAP group, 3 patients received methylphenidate, 1 received atomoxetine, and 1 received antidepressant medication. In the PE group, 2 patients took methylphenidate, and 2 participants took antidepressants.
• There was a significant difference regarding sex and response, with men experiencing less overall improvement than women.

Conclusions/limitations

• MAP was not superior to PE in terms of changes on CAARS scores, although within each group, both therapies showed improvement over time.
• While there may be gender-specific differences in processing information and coping strategies, future research should examine the differences between men and women with different therapeutic approaches.
• Limitations: This study did not employ a true placebo but instead had 2 active arms. Generalizability is limited due to a lack of certain comorbidities and use of medications.

Continue to: #3

 

 

3. Janssen L, Kan CC, Carpentier PJ, et al. Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial. Psychol Med. 2019;49(1):55-65. doi:10.1017/S0033291718000429

Mindfulness-based cognitive therapy (MBCT) is a form of psychotherapy that combines mindfulness with the principles of CBT. Hepark et al¹⁸ found benefits of MBCT for reducing ADHD symptoms. In a larger, multicenter, single-blind RCT, Janssen et al¹⁰ reviewed the efficacy of MBCT compared to treatment as usual (TAU).

Study design

• A total of 120 participants age ≥18 who met DSM-IV criteria for ADHD were recruited from Dutch clinics and advertisements and randomized to receive MBCT plus TAU (n = 60) or TAU alone (n = 60). There were no significant demographic differences between groups at baseline.
• Exclusion criteria included active depression with psychosis or suicidality, active manic episode, tic disorder with vocal tics, ASD, learning or other cognitive impairments, borderline or antisocial personality disorder, substance dependence, or previous participation in MBCT or other mindfulness-based interventions. Participants also had to be able to complete the questionnaires in Dutch.
• Blinded evaluations were conducted at baseline (T0), at the completion of therapy (T1), 3 months after the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• MBCT included 8 weekly, 2.5-hour sessions and a 6-hour silent session between the sixth and seventh sessions. Patients participated in various meditation techniques with the addition of PE, CBT, and group discussions. They were also instructed to practice guided exercises 6 days/week, for approximately 30 minutes/day.
• The primary outcome was change in ADHD symptoms as assessed by the investigator-rated CAARS (CAARS-INV) at T1.
• Secondary outcomes included change in scores on the CAARS: Screening Version (CAARS-S:SV), BRIEF-A, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF), Self-Compassion Scale-Short Form (SCS-SF), Mental Health Continuum-Short Form (MHC-SF), and Outcome Questionnaire (OQ 45.2).

Outcomes

• In the MBCT group, participants who dropped out (n = 9) were less likely to be using ADHD medication at baseline than those who completed the study.
• At T1, the MBCT plus TAU group had significantly less ADHD symptoms on CAARS-INV compared to TAU (d = 0.41, P = .004), with more participants in the MBCT plus TAU group experiencing a symptom reduction ≥30% (24% vs 7%, P = .001) and remission (P = .039).
• The MBCT plus TAU group also had a significant reduction in scores on CAARS-S:SV as well as significant improvement on self-compassion per SCS-SF, mindfulness skills per FFMQ-SF, and positive mental health per MHC-SF, but not on executive functioning per BRIEF-A or general functioning per OQ 45.2.
• Over 6-month follow-up, there continued to be significant improvement in CAARS-INV, CAARS-S:SV, mindfulness skills, self-compassion, and positive mental health in the MBCT plus TAU group compared to TAU. The difference in executive functioning (BRIEF-A) also became significant over time.

Conclusions/limitations

• MBCT plus TAU appears to be effective for reducing ADHD symptoms, both from a clinician-rated and self-reported perspective, with improvements lasting up to 6 months.
• There were also improvements in mindfulness, self-compassion, and positive mental health posttreatment in the MBCT plus TAU group, with improvement in executive functioning seen over the follow-up periods.
• Limitations: The sample was drawn solely from a Dutch population and did not assess the success of blinding.

Continue to: #4

 

 

4. Selaskowski B, Steffens M, Schulze M, et al. Smartphone-assisted psychoeducation in adult attention-deficit/hyperactivity disorder: a randomized controlled trial. Psychiatry Res. 2022;317:114802. doi:10.1016/j.psychres.2022.114802

Managing adult ADHD can include PE, but few studies have reviewed the effectiveness of formal clinical PE. PE is “systemic, didactic-psychotherapeutic interventions, which are adequate for informing patients and their relatives about the illness and its treatment, facilitating both an understanding and personally responsible handling of the illness and supporting those afflicted in coping with the disorder.”¹⁹ Selaskowski et al¹¹ investigated the feasibility of using smartphone-assisted PE (SAP) for adults diagnosed with ADHD.

Study design

• Participants were 60 adults age 18 to 65 who met DSM-5 diagnostic criteria for ADHD. They were required to have a working comprehension of the German language and access to an Android-powered smartphone.
• Exclusion criteria included a diagnosis of schizophrenia or other psychotic disorder, antisocial personality disorder, substance use disorder, severe affective disorder, severe neurologic disorder, or initial use or dose change of ADHD medications 2 weeks prior to baseline.
• Participants were randomized to SAP (n = 30) or brochure-assisted PE (BAP) (n = 30). The demographics at baseline were mostly balanced between the groups except for substance abuse (5 in the SAP group vs 0 in the BAP group; P = .022).
• The primary outcome was severity of total ADHD symptoms, which was assessed by blinded evaluations conducted at baseline (T0) and after 8 weekly PE sessions (T1).
• Secondary outcomes included dropout rates, improvement in depressive symptoms as measured by the German BDI-II, improvement in functional impairment as measured by the Weiss Functional Impairment Scale (WFIRS), homework performed, attendance, and obtained PE knowledge.
• Both groups attended 8 weekly 1-hour PE group sessions led by 2 therapists and comprised of 10 participants.

Outcomes

• Only 43 of the 60 initial participants completed the study; 24 in the SAP group and 19 in the BAP group.
• The SAP group experienced a significant symptom improvement of 33.4% from T0 to T1 compared to the BAP group, which experienced a symptom improvement of 17.3% (P = .019).
• ADHD core symptoms considerably decreased in both groups. There was no significant difference between groups (P = .74).
• SAP dramatically improved inattention (P = .019), improved impulsivity (P = .03), and increased completed homework (P < .001), compared to the BAP group.
• There was no significant difference in correctly answered quiz questions or in BDI-II or WFIRS scores.

Conclusions/limitations

• Both SAP and BAP appear to be effective methods for PE, but patients who participated in SAP showed greater improvements than those who participated in BAP.
• Limitations: This study lacked a control intervention that was substantially different from SAP and lacked follow-up. The sample was a mostly German population, participants were required to have smartphone access beforehand, and substance abuse was more common in the SAP group.

Continue to: #5

 

 

5. Pan MR, Huang F, Zhao MJ, et al. A comparison of efficacy between cognitive behavioral therapy (CBT) and CBT combined with medication in adults with attention-deficit/hyperactivity disorder (ADHD). Psychiatry Res. 2019;279:23-33. doi:10.1016/j.psychres.2019.06.040

CBT has demonstrated long-term benefit for the core symptoms of ADHD, comorbid symptoms (anxiety and depression), and social functioning. For ADHD, pharmacotherapies have a bottom-up effect where they increase neurotransmitter concentration, leading to an effect in the prefrontal lobe, whereas psychotherapies affect behavior-related brain activity in the prefrontal lobes, leading to the release of neurotransmitters. Pan et al¹² compared the benefits of CBT plus medication (CBT + M) to CBT alone on core ADHD symptoms, social functioning, and comorbid symptoms.

Study design

• The sample consisted of 124 participants age >18 who had received a diagnosis of adult ADHD according to DSM-IV via Conner’s Adult ADHD Diagnostic Interview and were either outpatients at Peking University Sixth Hospital or participants in a previous RCT (Huang et al²⁰).
• Exclusion criteria included organic mental disorders, high suicide risk in those with major depressive disorder, acute BD episode requiring medication or severe panic disorder or psychotic disorder requiring medication, pervasive developmental disorder, previous or current involvement in other psychological therapies, IQ <90, unstable physical conditions requiring medical treatment, attending <7 CBT sessions, or having serious adverse effects from medication.
• Participants received CBT + M (n = 57) or CBT alone (n = 67); 40 (70.18%) participants in the CBT + M group received methylphenidate hydrochloride controlled-release tablets (average dose 27.45 ± 9.97 mg) and 17 (29.82%) received atomoxetine hydrochloride (average dose 46.35 ± 20.09 mg). There were no significant demographic differences between groups.
• CBT consisted of 12 weekly 2-hour sessions (8 to 12 participants in each group) that were led by 2 trained psychiatrist therapists and focused on behavioral and cognitive strategies.
• Participants in the CBT alone group were drug-naïve and those in CBT + M group were stable on medications.
• The primary outcome was change in ADHD Rating Scale (ADHD-RS) score from baseline to Week 12.
• Secondary outcomes included Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Self-Esteem Scale (SES), executive functioning (BRIEF-A), and quality of life (World Health Organization Quality of Life-Brief version [WHOQOL-BREF]).

Outcomes

• ADHD-RS total, impulsiveness-hyperactivity subscale, and inattention subscale scores significantly improved in both groups (P < .01). The improvements were greater in the CBT + M group compared to the CBT-only group, but the differences were not statistically significant.
• There was no significant difference between groups in remission rate (P < .689).
• There was a significant improvement in SAS, SES, and SDS scores in both groups (P < .01).
• In terms of the WHOQOL-BREF, the CBT + M group experienced improvements only in the psychological and environmental domains, while the CBT-only group significantly improved across the board. The CBT-only group experienced greater improvement in the physical domain (P < .01).
• Both groups displayed considerable improvements in the Metacognition Index and Global Executive Composite for BRIEF-A. The shift, self-monitor, initiate, working memory, plan/organize, task monitor, and material organization skills significantly improved in the CBT + M group. The only areas where the CBT group significantly improved were initiate, material organization, and working memory. No significant differences in BRIEF-A effectiveness were discovered.

Conclusions/limitations

• CBT is an effective treatment for improving core ADHD symptoms.
• This study was unable to establish that CBT alone was preferable to CBT + M, particularly in terms of core symptoms, emotional symptoms, or self-esteem.
• CBT + M could lead to a greater improvement in executive function than CBT alone.
• Limitations: This study used previous databases rather than RCTs. There was no placebo in the CBT-only group. The findings may not be generalizable because participants had high education levels and IQ. The study lacked follow-up after 12 weeks.

Continue to: #6

 

 

6. van Andel E, Bijlenga D, Vogel SWN, et al. Effects of chronotherapy on circadian rhythm and ADHD symptoms in adults with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome: a randomized clinical trial. Chronobiol Int. 2021;38(2):260-269. doi:10.1080/07420528.2020.1835943

Most individuals with ADHD have a delayed circadian rhythm.²¹ Delayed sleep phase syndrome (DSPS) is diagnosed when a persistently delayed circadian rhythm is not brought on by other diseases or medications. ADHD symptoms and circadian rhythm may both benefit from DSPS treatment. A 3-armed randomized clinical parallel-group trial by van Andel et al¹³ investigated the effects of chronotherapy on ADHD symptoms and circadian rhythm.

Study design

• Participants were Dutch-speaking individuals age 18 to 55 who were diagnosed with ADHD and DSPS. They were randomized to receive melatonin 0.5 mg/d (n = 17), placebo (n = 17), or melatonin 0.5 mg/d plus 30 minutes of timed morning bright light therapy (BLT) (n = 15) daily for 3 weeks. There were no significant differences in baseline characteristics between groups except that the melatonin plus BLT group had higher use of oral contraceptives (P = .007).
• This study was completed in the Netherlands with participants from an outpatient adult ADHD clinic.
• Exclusion criteria included epilepsy, psychotic disorders, anxiety or depression requiring acute treatment, alcohol intake >15 units/week in women or >21 units/week in men, ADHD medications, medications affecting sleep, use of drugs, mental retardation, amnestic disorder, dementia, cognitive dysfunction, crossed >2 time zones in the 2 weeks prior to the study, shift work within the previous month, having children disturbing sleep, glaucoma, retinopathy, having BLT within the previous month, pregnancy, lactation, or trying to conceive.
• The study consisted of 3-armed placebo-controlled parallel groups in which 2 were double-blind (melatonin group and placebo group).
• During the first week of treatment, medication was taken 3 hours before dim-light melatonin onset (DLMO) and later advanced to 4 and 5 hours in Week 2 and Week 3, respectively. BLT was used at 20 cm from the eyes for 30 minutes every morning between 7 am and 8 am.
• The primary outcome was DLMO in which radioimmunoassay was used to determine melatonin concentrations. DLMO was used as a marker for internal circadian rhythm.
• The secondary outcome was ADHD symptoms using the Dutch version of the ADHD Rating Scale-IV.
• Evaluations were conducted at baseline (T0), the conclusion of treatment (T1), and 2 weeks after the end of treatment (T2).

Outcomes

• Out of 51 participants, 2 dropped out of the melatonin plus BLT group before baseline, and 3 dropped out of the placebo group before T1.
• At baseline, the average DLMO was 11:43 pm ± 1 hour and 46 minutes, with 77% of participants experiencing DLMO after 11 pm. Melatonin advanced DLMO by 1 hour and 28 minutes (P = .001) and melatonin plus BLT had an advance of 1 hour and 58 minutes (P < .001). DLMO was unaffected by placebo.
• The melatonin group experienced a 14% reduction in ADHD symptoms (P = .038); the placebo and melatonin plus BLT groups did not experience a reduction.
• DLMO and ADHD symptoms returned to baseline 2 weeks after therapy ended.

Conclusions/limitations

• In patients with DSPS and ADHD, low-dose melatonin can improve internal circadian rhythm and decrease ADHD symptoms.
• Melatonin plus BLT was not effective in improving ADHD symptoms or advancing DLMO.
• Limitations: This study used self-reported measures for ADHD symptoms. The generalizability of the findings is limited because the exclusion criteria led to minimal comorbidity. The sample was comprised of a mostly Dutch population.

SECOND OF 2 PARTS

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional impairment.¹ ADHD begins in childhood, continues into adulthood, and has negative consequences in many facets of adult patients’ lives, including their careers, daily functioning, and interpersonal relationships.² According to the National Institute of Health and Care Excellence’s recommendations, both pharmacotherapy and psychotherapy are advised for patients with ADHD.³ Although various pharmacotherapies are advised as first-line treatments for ADHD, they are frequently linked to unfavorable adverse effects, partial responses, chronic residual symptoms, high dropout rates, and issues with addiction.⁴ As a result, there is a need for evidence-based nonpharmacologic therapies.

In a systematic review, Nimmo-Smith et al⁵ found that certain nonpharmacologic treatments can be effective in helping patients with ADHD manage their illness. In clinical and cognitive assessments of ADHD, a recent meta-analysis found that noninvasive brain stimulation had a small but significant effect.⁶ Some evidence suggests that in addition to noninvasive brain stimulation, other nonpharmacologic interventions, including psychoeducation (PE), mindfulness, cognitive-behavioral therapy (CBT), and chronotherapy, can be effective as an adjunct treatment to pharmacotherapy, and possibly as monotherapy.

Part 1 of this 2-part article reviewed 6 randomized controlled trials (RCTs) of pharmacologic interventions for adult ADHD published within the last 5 years.⁷ Part 2 analyzes 6 RCTs of nonpharmacologic treatments for adult ADHD published within the last 5 years (Table^8-13).

1. Leffa DT, Grevet EH, Bau CHD, et al. Transcranial direct current stimulation vs sham for the treatment of inattention in adults with attention-deficit/hyperactivity disorder: the TUNED randomized clinical trial. JAMA Psychiatry. 2022;79(9):847-856. doi:10.1001/jamapsychiatry.2022.2055

Transcranial direct current stimulation (tDCS) uses noninvasive, low-intensity electrical current on the scalp to affect underlying cortical activity.¹⁴ This form of neurostimulation offers an alternative treatment option for when medications fail or are not tolerated, and can be used at home without the direct involvement of a clinician.¹⁴ tDCS as a treatment for ADHD has been increasingly researched, though many studies have been limited by short treatment periods and varied methodological approaches. In a meta-analysis, Westwood et al⁶ found a trend toward improvement on the function of processing speed but not on attention. Leffa et al⁸ examined the efficacy and safety of a 4-week course of home-based tDCS in adult patients with ADHD, specifically looking at reduction in inattention symptoms.

Study design

• This randomized, double-blind, parallel, sham-controlled clinical trial evaluated 64 participants age 18 to 60 from a single center in Brazil who met DSM-5 criteria for combined or primarily inattentive ADHD.
• Inclusion criteria included an inattention score ≥21 on the clinician-administered Adult ADHD Self-report Scale version 1.1 (CASRS). This scale assesses both inattentive symptoms (CASRS-I) and hyperactive-impulsive symptoms (CASRS-HI). Participants were not being treated with stimulants or agreed to undergo a 30-day washout of stimulants prior to the study.
• Exclusion criteria included current moderate to severe depression (Beck Depression Inventory-II [BDI] score >21), current moderate to severe anxiety (Beck Anxiety Inventory [BAI] score ≥21), diagnosis of bipolar disorder (BD) with either a manic or depressive episode in the year prior to study, diagnosis of a psychotic disorder, diagnosis of autism spectrum disorder (ASD), positive screen for substance use, unstable medical condition resulting in poor functionality, pregnant or planning on becoming pregnant within 3 months of the study, not able to use home-based equipment, history of neurosurgery, presence of ferromagnetic metal in the head or presence of implanted medical devices in head/neck region, or history of epilepsy with reported seizures in the year prior to the study.
• Participants were randomized to self-administer real or sham tDCS; the devices looked the same. Participants underwent daily 30-minute sessions using a 2-mA direct constant current for a total of 28 sessions. Sham treatment involved a 30-second ramp-up to 2-mA and a 30-second ramp-down sensation at the beginning, middle, and end of each respective session.
• The primary outcome was a change in symptoms of inattention per CASRS-I. Secondary outcomes were scores on the CASRS-HI, BDI, BAI, and Behavior Rating Inventory of Executive Functions-Adult (BRIEF-A), which evaluates executive function.

Outcomes

• A total of 53 participants used stimulant medications prior to the study and 8 required a washout. The average age was 38.3, and 53% of participants were male.
• For the 55 participants who completed 4 weeks of treatment, the mean number of sessions was 25.2 in the tDCS group and 24.8 in the sham group.
• At the end of Week 4, there was a statistically significant treatment by time interaction in CASRS-I scores in the tDCS group compared to the sham group (18.88 vs 23.63 on final CASRS-I scores; P < .001).
• There were no statistically significant differences in any of the secondary outcomes.

Conclusions/limitations

• This study showed the benefits of 4 weeks of home-based tDCS for managing inattentive symptoms in adults with ADHD. The authors noted that extended treatment of tDCS may incur greater benefit, as this study used a longer treatment course compared to others that have used a shorter duration of treatment (ie, days instead of weeks). Additionally, this study placed the anodal electrode over the right dorsolateral prefrontal cortex (DLPFC) vs over the left DLPFC, because there may be a decrease in activation in the right DLPFC in adults with ADHD undergoing attention tasks.¹⁵
• This study also showed that home-based tDCS can be an easier and more accessible way for patients to receive treatment, as opposed to needing to visit a health care facility.
• Limitations: The dropout rate (although only 2 of 7 participants who dropped out of the active group withdrew due to adverse events), lack of remote monitoring of patients, and restrictive inclusion criteria limit the generalizability of these findings. Additionally, 3 patients in the tDCS group and 7 in the sham group were taking psychotropic medications for anxiety or depression.

Continue to: #2

 

 

2. Hoxhaj E, Sadohara C, Borel P, et al. Mindfulness vs psychoeducation in adult ADHD: a randomized controlled trial. Eur Arch Psychiatry Clin Neurosci. 2018;268(4):321-335. doi:10.1007/s00406-018-0868-4

Previous research has shown that using mindfulness-based approaches can improve ADHD symptoms.^16,17 Hoxhaj et al⁹ looked at the effectiveness of mindfulness awareness practices (MAP) for alleviating ADHD symptoms.

Study design

• This RCT enrolled 81 adults from a German medical center who met DSM-IV criteria for ADHD, were not taking any ADHD medications, and had not undergone any psychotherapeutic treatments in the last 3 months. Participants were randomized to receive MAP (n = 41) or PE (n = 40).
• Exclusion criteria included having a previous diagnosis of schizophrenia, BD I, active substance dependence, ASD, suicidality, self-injurious behavior, or neurologic disorders.
• The MAP group underwent 8 weekly 2.5-hour sessions, plus homework involving meditation and other exercises. The PE group was given information regarding ADHD and management options, including organization and stress management skills.
• Patients were assessed 2 weeks before treatment (T1), at the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• The primary outcome was the change in the blind-observer rated Conner’s Adult ADHD Rating Scales (CAARS) inattention/memory scales from T1 to T2.
• Secondary outcomes included the other CAARS subscales, the Brief Symptom Inventory (BSI), the BDI, the 36-item Short Form Health Survey, and the Five Facet Mindfulness Questionnaire (FFMQ).

Outcomes

• Baseline demographics did not differ between groups other than the MAP group having a significantly higher IQ than the PE group. However, this difference resolved after the final sample was analyzed, as there were 2 dropouts and 7 participants lost to follow-up in the MAP group and 4 dropouts and 4 participants lost to follow-up in the PE group.
• There was no significant difference between the groups in the primary outcome of observer-rated CAARS inattention/memory subscale scores, or other ADHD symptoms per the CAARS.
• However, there was a significant difference within each group on all ADHD subscales of the observer-rated CAARS at T2. Persistent, significant differences were noted for the observer-rated CAARS subscales of self-concept and DSM-IV Inattentive Symptoms, and all CAARS self-report scales to T3.
• Compared to the PE group, there was a significantly larger improvement in the MAP group on scores of the mindfulness parameters of observation and nonreactivity to inner experience.
• There were significant improvements regarding depression per the BDI and global severity per the BSI in both treatment groups, with no differences between the groups.
• At T3, in the MAP group, 3 patients received methylphenidate, 1 received atomoxetine, and 1 received antidepressant medication. In the PE group, 2 patients took methylphenidate, and 2 participants took antidepressants.
• There was a significant difference regarding sex and response, with men experiencing less overall improvement than women.

Conclusions/limitations

• MAP was not superior to PE in terms of changes on CAARS scores, although within each group, both therapies showed improvement over time.
• While there may be gender-specific differences in processing information and coping strategies, future research should examine the differences between men and women with different therapeutic approaches.
• Limitations: This study did not employ a true placebo but instead had 2 active arms. Generalizability is limited due to a lack of certain comorbidities and use of medications.

Continue to: #3

 

 

3. Janssen L, Kan CC, Carpentier PJ, et al. Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial. Psychol Med. 2019;49(1):55-65. doi:10.1017/S0033291718000429

Mindfulness-based cognitive therapy (MBCT) is a form of psychotherapy that combines mindfulness with the principles of CBT. Hepark et al¹⁸ found benefits of MBCT for reducing ADHD symptoms. In a larger, multicenter, single-blind RCT, Janssen et al¹⁰ reviewed the efficacy of MBCT compared to treatment as usual (TAU).

Study design

• A total of 120 participants age ≥18 who met DSM-IV criteria for ADHD were recruited from Dutch clinics and advertisements and randomized to receive MBCT plus TAU (n = 60) or TAU alone (n = 60). There were no significant demographic differences between groups at baseline.
• Exclusion criteria included active depression with psychosis or suicidality, active manic episode, tic disorder with vocal tics, ASD, learning or other cognitive impairments, borderline or antisocial personality disorder, substance dependence, or previous participation in MBCT or other mindfulness-based interventions. Participants also had to be able to complete the questionnaires in Dutch.
• Blinded evaluations were conducted at baseline (T0), at the completion of therapy (T1), 3 months after the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• MBCT included 8 weekly, 2.5-hour sessions and a 6-hour silent session between the sixth and seventh sessions. Patients participated in various meditation techniques with the addition of PE, CBT, and group discussions. They were also instructed to practice guided exercises 6 days/week, for approximately 30 minutes/day.
• The primary outcome was change in ADHD symptoms as assessed by the investigator-rated CAARS (CAARS-INV) at T1.
• Secondary outcomes included change in scores on the CAARS: Screening Version (CAARS-S:SV), BRIEF-A, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF), Self-Compassion Scale-Short Form (SCS-SF), Mental Health Continuum-Short Form (MHC-SF), and Outcome Questionnaire (OQ 45.2).

Outcomes

• In the MBCT group, participants who dropped out (n = 9) were less likely to be using ADHD medication at baseline than those who completed the study.
• At T1, the MBCT plus TAU group had significantly less ADHD symptoms on CAARS-INV compared to TAU (d = 0.41, P = .004), with more participants in the MBCT plus TAU group experiencing a symptom reduction ≥30% (24% vs 7%, P = .001) and remission (P = .039).
• The MBCT plus TAU group also had a significant reduction in scores on CAARS-S:SV as well as significant improvement on self-compassion per SCS-SF, mindfulness skills per FFMQ-SF, and positive mental health per MHC-SF, but not on executive functioning per BRIEF-A or general functioning per OQ 45.2.
• Over 6-month follow-up, there continued to be significant improvement in CAARS-INV, CAARS-S:SV, mindfulness skills, self-compassion, and positive mental health in the MBCT plus TAU group compared to TAU. The difference in executive functioning (BRIEF-A) also became significant over time.

Conclusions/limitations

• MBCT plus TAU appears to be effective for reducing ADHD symptoms, both from a clinician-rated and self-reported perspective, with improvements lasting up to 6 months.
• There were also improvements in mindfulness, self-compassion, and positive mental health posttreatment in the MBCT plus TAU group, with improvement in executive functioning seen over the follow-up periods.
• Limitations: The sample was drawn solely from a Dutch population and did not assess the success of blinding.

Continue to: #4

 

 

4. Selaskowski B, Steffens M, Schulze M, et al. Smartphone-assisted psychoeducation in adult attention-deficit/hyperactivity disorder: a randomized controlled trial. Psychiatry Res. 2022;317:114802. doi:10.1016/j.psychres.2022.114802

Managing adult ADHD can include PE, but few studies have reviewed the effectiveness of formal clinical PE. PE is “systemic, didactic-psychotherapeutic interventions, which are adequate for informing patients and their relatives about the illness and its treatment, facilitating both an understanding and personally responsible handling of the illness and supporting those afflicted in coping with the disorder.”¹⁹ Selaskowski et al¹¹ investigated the feasibility of using smartphone-assisted PE (SAP) for adults diagnosed with ADHD.

Study design

• Participants were 60 adults age 18 to 65 who met DSM-5 diagnostic criteria for ADHD. They were required to have a working comprehension of the German language and access to an Android-powered smartphone.
• Exclusion criteria included a diagnosis of schizophrenia or other psychotic disorder, antisocial personality disorder, substance use disorder, severe affective disorder, severe neurologic disorder, or initial use or dose change of ADHD medications 2 weeks prior to baseline.
• Participants were randomized to SAP (n = 30) or brochure-assisted PE (BAP) (n = 30). The demographics at baseline were mostly balanced between the groups except for substance abuse (5 in the SAP group vs 0 in the BAP group; P = .022).
• The primary outcome was severity of total ADHD symptoms, which was assessed by blinded evaluations conducted at baseline (T0) and after 8 weekly PE sessions (T1).
• Secondary outcomes included dropout rates, improvement in depressive symptoms as measured by the German BDI-II, improvement in functional impairment as measured by the Weiss Functional Impairment Scale (WFIRS), homework performed, attendance, and obtained PE knowledge.
• Both groups attended 8 weekly 1-hour PE group sessions led by 2 therapists and comprised of 10 participants.

Outcomes

• Only 43 of the 60 initial participants completed the study; 24 in the SAP group and 19 in the BAP group.
• The SAP group experienced a significant symptom improvement of 33.4% from T0 to T1 compared to the BAP group, which experienced a symptom improvement of 17.3% (P = .019).
• ADHD core symptoms considerably decreased in both groups. There was no significant difference between groups (P = .74).
• SAP dramatically improved inattention (P = .019), improved impulsivity (P = .03), and increased completed homework (P < .001), compared to the BAP group.
• There was no significant difference in correctly answered quiz questions or in BDI-II or WFIRS scores.

Conclusions/limitations

• Both SAP and BAP appear to be effective methods for PE, but patients who participated in SAP showed greater improvements than those who participated in BAP.
• Limitations: This study lacked a control intervention that was substantially different from SAP and lacked follow-up. The sample was a mostly German population, participants were required to have smartphone access beforehand, and substance abuse was more common in the SAP group.

Continue to: #5

 

 

5. Pan MR, Huang F, Zhao MJ, et al. A comparison of efficacy between cognitive behavioral therapy (CBT) and CBT combined with medication in adults with attention-deficit/hyperactivity disorder (ADHD). Psychiatry Res. 2019;279:23-33. doi:10.1016/j.psychres.2019.06.040

CBT has demonstrated long-term benefit for the core symptoms of ADHD, comorbid symptoms (anxiety and depression), and social functioning. For ADHD, pharmacotherapies have a bottom-up effect where they increase neurotransmitter concentration, leading to an effect in the prefrontal lobe, whereas psychotherapies affect behavior-related brain activity in the prefrontal lobes, leading to the release of neurotransmitters. Pan et al¹² compared the benefits of CBT plus medication (CBT + M) to CBT alone on core ADHD symptoms, social functioning, and comorbid symptoms.

Study design

• The sample consisted of 124 participants age >18 who had received a diagnosis of adult ADHD according to DSM-IV via Conner’s Adult ADHD Diagnostic Interview and were either outpatients at Peking University Sixth Hospital or participants in a previous RCT (Huang et al²⁰).
• Exclusion criteria included organic mental disorders, high suicide risk in those with major depressive disorder, acute BD episode requiring medication or severe panic disorder or psychotic disorder requiring medication, pervasive developmental disorder, previous or current involvement in other psychological therapies, IQ <90, unstable physical conditions requiring medical treatment, attending <7 CBT sessions, or having serious adverse effects from medication.
• Participants received CBT + M (n = 57) or CBT alone (n = 67); 40 (70.18%) participants in the CBT + M group received methylphenidate hydrochloride controlled-release tablets (average dose 27.45 ± 9.97 mg) and 17 (29.82%) received atomoxetine hydrochloride (average dose 46.35 ± 20.09 mg). There were no significant demographic differences between groups.
• CBT consisted of 12 weekly 2-hour sessions (8 to 12 participants in each group) that were led by 2 trained psychiatrist therapists and focused on behavioral and cognitive strategies.
• Participants in the CBT alone group were drug-naïve and those in CBT + M group were stable on medications.
• The primary outcome was change in ADHD Rating Scale (ADHD-RS) score from baseline to Week 12.
• Secondary outcomes included Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Self-Esteem Scale (SES), executive functioning (BRIEF-A), and quality of life (World Health Organization Quality of Life-Brief version [WHOQOL-BREF]).

Outcomes

• ADHD-RS total, impulsiveness-hyperactivity subscale, and inattention subscale scores significantly improved in both groups (P < .01). The improvements were greater in the CBT + M group compared to the CBT-only group, but the differences were not statistically significant.
• There was no significant difference between groups in remission rate (P < .689).
• There was a significant improvement in SAS, SES, and SDS scores in both groups (P < .01).
• In terms of the WHOQOL-BREF, the CBT + M group experienced improvements only in the psychological and environmental domains, while the CBT-only group significantly improved across the board. The CBT-only group experienced greater improvement in the physical domain (P < .01).
• Both groups displayed considerable improvements in the Metacognition Index and Global Executive Composite for BRIEF-A. The shift, self-monitor, initiate, working memory, plan/organize, task monitor, and material organization skills significantly improved in the CBT + M group. The only areas where the CBT group significantly improved were initiate, material organization, and working memory. No significant differences in BRIEF-A effectiveness were discovered.

Conclusions/limitations

• CBT is an effective treatment for improving core ADHD symptoms.
• This study was unable to establish that CBT alone was preferable to CBT + M, particularly in terms of core symptoms, emotional symptoms, or self-esteem.
• CBT + M could lead to a greater improvement in executive function than CBT alone.
• Limitations: This study used previous databases rather than RCTs. There was no placebo in the CBT-only group. The findings may not be generalizable because participants had high education levels and IQ. The study lacked follow-up after 12 weeks.

Continue to: #6

 

 

6. van Andel E, Bijlenga D, Vogel SWN, et al. Effects of chronotherapy on circadian rhythm and ADHD symptoms in adults with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome: a randomized clinical trial. Chronobiol Int. 2021;38(2):260-269. doi:10.1080/07420528.2020.1835943

Most individuals with ADHD have a delayed circadian rhythm.²¹ Delayed sleep phase syndrome (DSPS) is diagnosed when a persistently delayed circadian rhythm is not brought on by other diseases or medications. ADHD symptoms and circadian rhythm may both benefit from DSPS treatment. A 3-armed randomized clinical parallel-group trial by van Andel et al¹³ investigated the effects of chronotherapy on ADHD symptoms and circadian rhythm.

Study design

• Participants were Dutch-speaking individuals age 18 to 55 who were diagnosed with ADHD and DSPS. They were randomized to receive melatonin 0.5 mg/d (n = 17), placebo (n = 17), or melatonin 0.5 mg/d plus 30 minutes of timed morning bright light therapy (BLT) (n = 15) daily for 3 weeks. There were no significant differences in baseline characteristics between groups except that the melatonin plus BLT group had higher use of oral contraceptives (P = .007).
• This study was completed in the Netherlands with participants from an outpatient adult ADHD clinic.
• Exclusion criteria included epilepsy, psychotic disorders, anxiety or depression requiring acute treatment, alcohol intake >15 units/week in women or >21 units/week in men, ADHD medications, medications affecting sleep, use of drugs, mental retardation, amnestic disorder, dementia, cognitive dysfunction, crossed >2 time zones in the 2 weeks prior to the study, shift work within the previous month, having children disturbing sleep, glaucoma, retinopathy, having BLT within the previous month, pregnancy, lactation, or trying to conceive.
• The study consisted of 3-armed placebo-controlled parallel groups in which 2 were double-blind (melatonin group and placebo group).
• During the first week of treatment, medication was taken 3 hours before dim-light melatonin onset (DLMO) and later advanced to 4 and 5 hours in Week 2 and Week 3, respectively. BLT was used at 20 cm from the eyes for 30 minutes every morning between 7 am and 8 am.
• The primary outcome was DLMO in which radioimmunoassay was used to determine melatonin concentrations. DLMO was used as a marker for internal circadian rhythm.
• The secondary outcome was ADHD symptoms using the Dutch version of the ADHD Rating Scale-IV.
• Evaluations were conducted at baseline (T0), the conclusion of treatment (T1), and 2 weeks after the end of treatment (T2).

Outcomes

• Out of 51 participants, 2 dropped out of the melatonin plus BLT group before baseline, and 3 dropped out of the placebo group before T1.
• At baseline, the average DLMO was 11:43 pm ± 1 hour and 46 minutes, with 77% of participants experiencing DLMO after 11 pm. Melatonin advanced DLMO by 1 hour and 28 minutes (P = .001) and melatonin plus BLT had an advance of 1 hour and 58 minutes (P < .001). DLMO was unaffected by placebo.
• The melatonin group experienced a 14% reduction in ADHD symptoms (P = .038); the placebo and melatonin plus BLT groups did not experience a reduction.
• DLMO and ADHD symptoms returned to baseline 2 weeks after therapy ended.

Conclusions/limitations

• In patients with DSPS and ADHD, low-dose melatonin can improve internal circadian rhythm and decrease ADHD symptoms.
• Melatonin plus BLT was not effective in improving ADHD symptoms or advancing DLMO.
• Limitations: This study used self-reported measures for ADHD symptoms. The generalizability of the findings is limited because the exclusion criteria led to minimal comorbidity. The sample was comprised of a mostly Dutch population.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.¹ ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.² Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.³ The overall prevalence of adult ADHD is 4.4%.⁴ ADHD in adults is frequently associated with comorbid psychiatric disorders.⁵ The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.¹

Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,⁶ with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.⁷ This could be due to inadequate response or adverse effects.⁸ Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.⁶ Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.

In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table^9-14). Part 2 will review nonpharmacologic treatments.

1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980

The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.¹⁵ It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al⁹ performed a follow-up analysis of the COMPAS trial.

Study design

• This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
• The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
• The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
• The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
• COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.

Outcomes

• A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
• Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
• The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
• Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
• There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
• Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
• Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
• Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).

2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w

In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al¹⁰ reviewed the safety and efficacy of viloxazine ER in adults with ADHD.

Study design

• This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
• Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m², and being medically healthy.
• Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
• The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
• All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
• The primary outcome was a change in AISRS score from baselines to Week 6.
• The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.

Outcomes

• Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
• The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
• The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
• Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
• The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
• Viloxazine ER was well tolerated and safe.
• Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.

3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851

Kis et al¹¹ analyzed the safety results of COMPAS.¹⁵ Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.⁹

Study design

• Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
• AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
• The sample size was assessed to have 80% power to detect group differences in AEs.

Outcomes

• Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
• AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
• There were no significant differences in AEs between the GPT and CM groups.
• The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
• Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
• There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
• Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.

4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438

Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,¹⁶ can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al¹² looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.

Study design

• This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
• Women were not lactating or pregnant during the study.
• Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
• Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10 am. Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks.
• The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
• Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.

Outcomes

• Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
• Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
• The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
• The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
• The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
• No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
• The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
• Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.

5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979

Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.¹⁷ Iwanami et al¹³ evaluated the efficacy and safety of GXR for adults.

Study design

• This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
• Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardio­vascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
• Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
• There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
• Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
• The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
• Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).

Outcomes

• The average GXR dose during the maintenance period was 5.07 mg/d.
• Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
• At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
• There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
• There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
• At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
• Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
• Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
• The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
• Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.

6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592

While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el¹⁴ assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.

Study design

• This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
• Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
• Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
• The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
• Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
• Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
• The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.

Outcomes

• Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
• Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
• ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
• For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
• For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
• For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
• As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
• There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).

Conclusions/limitations

• Stimulant-naive patients experienced no improvement with adjunctive BXP.
• For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
• The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
• BXP appeared to be well tolerated.
• Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.

Bottom Line

Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.

Related Resources

• Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
• Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268

Drug Brand Names

Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.¹ ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.² Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.³ The overall prevalence of adult ADHD is 4.4%.⁴ ADHD in adults is frequently associated with comorbid psychiatric disorders.⁵ The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.¹

Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,⁶ with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.⁷ This could be due to inadequate response or adverse effects.⁸ Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.⁶ Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.

In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table^9-14). Part 2 will review nonpharmacologic treatments.

1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980

The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.¹⁵ It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al⁹ performed a follow-up analysis of the COMPAS trial.

Study design

• This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
• The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
• The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
• The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
• COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.

Outcomes

• A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
• Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
• The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
• Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
• There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
• Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
• Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
• Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).

2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w

In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al¹⁰ reviewed the safety and efficacy of viloxazine ER in adults with ADHD.

Study design

• This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
• Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m², and being medically healthy.
• Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
• The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
• All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
• The primary outcome was a change in AISRS score from baselines to Week 6.
• The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.

Outcomes

• Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
• The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
• The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
• Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
• The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
• Viloxazine ER was well tolerated and safe.
• Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.

3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851

Kis et al¹¹ analyzed the safety results of COMPAS.¹⁵ Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.⁹

Study design

• Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
• AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
• The sample size was assessed to have 80% power to detect group differences in AEs.

Outcomes

• Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
• AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
• There were no significant differences in AEs between the GPT and CM groups.
• The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
• Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
• There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
• Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.

4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438

Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,¹⁶ can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al¹² looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.

Study design

• This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
• Women were not lactating or pregnant during the study.
• Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
• Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10 am. Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks.
• The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
• Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.

Outcomes

• Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
• Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
• The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
• The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
• The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
• No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
• The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
• Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.

5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979

Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.¹⁷ Iwanami et al¹³ evaluated the efficacy and safety of GXR for adults.

Study design

• This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
• Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardio­vascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
• Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
• There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
• Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
• The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
• Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).

Outcomes

• The average GXR dose during the maintenance period was 5.07 mg/d.
• Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
• At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
• There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
• There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
• At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
• Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
• Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
• The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
• Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.

6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592

While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el¹⁴ assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.

Study design

• This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
• Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
• Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
• The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
• Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
• Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
• The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.

Outcomes

• Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
• Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
• ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
• For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
• For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
• For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
• As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
• There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).

Conclusions/limitations

• Stimulant-naive patients experienced no improvement with adjunctive BXP.
• For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
• The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
• BXP appeared to be well tolerated.
• Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.

Bottom Line

Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.

Related Resources

• Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
• Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268

Drug Brand Names

Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that begins in childhood and continues into adulthood. The clinical presentation is characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional interference.¹ ADHD affects patients’ interpersonal and professional lives as well as their daily functioning.² Adults with ADHD may suffer from excessive self-criticism, low self-esteem, and sensitivity to criticism.³ The overall prevalence of adult ADHD is 4.4%.⁴ ADHD in adults is frequently associated with comorbid psychiatric disorders.⁵ The diagnosis of ADHD in adults requires the presence of ≥5 symptoms of inattention and hyperactivity/impulsivity that persist for ≥6 months. Patients must have first had such symptoms before age 12; symptoms need to be present in ≥2 settings and interfere with functioning.¹

Treatment of ADHD includes pharmacologic and nonpharmacologic interventions. For most patients, pharmacotherapy—specifically stimulant medications—is advised as first-line treatment,⁶ with adequate trials of methylphenidate and amphetamines before using second-line agents such as nonstimulants. However, despite these medications’ efficacy in randomized controlled trials (RCTs), adherence is low.⁷ This could be due to inadequate response or adverse effects.⁸ Guidelines also recommend the use of nonpharmacologic interventions for adults who cannot adhere to or tolerate medication or have an inadequate response.⁶ Potential nonpharmacologic interventions include transcranial direct current stimulation, mindfulness, psychoeducation, cognitive-behavioral therapy, and chronotherapy.

In Part 1 of this 2-part article, we review 6 RCTs of pharmacologic interventions for adult ADHD published within the last 5 years (Table^9-14). Part 2 will review nonpharmacologic treatments.

1. Lam AP, Matthies S, Graf E, et al; Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS Trial. JAMA Netw Open. 2019;2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980

The Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) was a multicenter prospective, randomized trial of adults age 18 to 58 with ADHD.¹⁵ It compared cognitive-behavioral group psychotherapy (GPT) with individual clinical management (CM), and methylphenidate with placebo. When used in conjunction with methylphenidate, psychological treatments produced better results than placebo. However, studies on the long-term effects of multimodal treatment in ADHD are limited. Lam et al⁹ performed a follow-up analysis of the COMPAS trial.

Study design

• This observer-masked study involved a follow-up of participants in COMPAS 1.5 years after the interventions were terminated. Of the 433 adults with ADHD who participated in COMPAS, 256 participated in this follow-up.
• The inclusion criteria of COMPAS were age 18 to 58; diagnosis of ADHD according to DSM-IV criteria; chronic course of ADHD symptoms from childhood to adulthood; a Wender Utah Rating Scale short version score ≥30; and no pathological abnormality detected on physical examination.
• The exclusion criteria were having an IQ <85; schizophrenia, bipolar disorder (BD), borderline personality disorder, antisocial personality disorder, suicidal or self-injurious behavior, autism, motor tics, or Tourette syndrome; substance abuse/dependence within 6 months prior to screening; positive drug screening; neurologic diseases, seizures, glaucoma, diabetes, hyperlipidemia, uncontrolled arterial hypertension, angina pectoris, tachycardia arrhythmia, or arterial occlusive disease; previous stroke; current bulimia or anorexia; low weight (body mass index [BMI] <20; pregnancy (current or planned) or breastfeeding; treatment with stimulants or ADHD-specific psychotherapy in the past 6 months; methylphenidate intolerance; treatment with antidepressants, norepinephrine reuptake inhibitors, bupropion, antipsychotics, theophylline, amantadine, anticoagulants derived from coumarin, antacids, or alpha-adrenergic agonists in the 2 weeks prior to baseline; and treatment with fluoxetine or monoamine oxidase inhibitors in the 4 weeks prior to baseline.
• The primary outcome was a change from baseline on the ADHD Index of Conners Adult ADHD Rating Scale (CAARS) score. Secondary outcomes were self-ratings on the Beck Depression Inventory (BDI) and observer-masked ratings of the Clinical Global Impression (CGI) scale and other ADHD rating scale scores, such as the Diagnostic Checklist for the diagnosis of ADHD in adults (ADHD-DC) and subscales of the CAARS.
• COMPAS was open regarding patient and therapist assignment to GPT and CM, but double-masked regarding medication. The statistical analysis focused on the 2x2 comparison of GPT vs CM and methylphenidate vs placebo.

Outcomes

• A total of 251 participants had an assessment with the observer-masked CAARS score. The baseline mean (SD) age was 36.3 (10.1), and approximately one-half (49.8%) of participants were male.
• Overall, 9.2% of patients took methylphenidate >31 days from termination of COMPAS before this study but not at the start of this study. Approximately one-third (31.1%) of patients were taking methylphenidate at follow-up. The mean (SD) daily dosage of methylphenidate was 36 (24.77) mg and 0.46 (0.27) mg/kg of body weight.
• The baseline all-group mean ADHD Index of CAARS score was 20.6. At follow-up, it was 14.7 for the CM arm and 14.2 for the GPT arm (difference not significant, P = .48). The mean score decreased to 13.8 for the methylphenidate arm and to 15.2 for the placebo (significant difference, P = .04).
• Overall, methylphenidate was associated with greater improvement in symptoms than placebo. Patients in the GPT arm had fewer severe symptoms as assessed by the self-reported ADHD Symptoms Total Score compared to the CM arm (P = .04).
• There were no significant differences in self-rating CAARS and observer-rated CAARS subscale scores. Compared to CM, GPT significantly decreased pure hyperactive symptoms on the ADHD-DC (P = .08). No significant differences were observed in BDI scores. The difference between GPT and CM remained significant at follow-up in terms of the CGI evaluation of efficacy (P = .04).

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Regardless of which combined treatments they received, patients with ADHD continued to improve 1.5 years after the 52-week treatment phase ended.
• Patients assigned to methylphenidate performed considerably better on the observer-rated CAARS than patients assigned to placebo.
• Benefits from GPT or CM in addition to methylphenidate therapy lasted 1.5 years. Compared to CM, GPT was not linked to better scores on the CAARS.
• Limitations: Approximately 41% of patients who were recruited did not participate. Daily functioning was measured only by the CGI. There were only marginal differences among the 4 treatments, and the study compared a very regimented approach (GPT) with one that was less focused (CM).

2. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double‐blind, placebo‐controlled trial assessing the efficacy and safety of viloxazine extended‐release capsules in adults with attention‐deficit/hyperactivity disorder. CNS Drugs. 2022;36(8): 897-915. doi:10.1007/s40263-022-00938-w

In 2021, the FDA approved viloxazine extended-release (ER) for treating ADHD in children and adolescents (age 6 to 17). Nasser et al¹⁰ reviewed the safety and efficacy of viloxazine ER in adults with ADHD.

Study design

• This phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial included 374 adults with ADHD who received viloxazine ER or placebo.
• Participants were age 18 to 65 and had been given a primary diagnosis of ADHD according to DSM-5 criteria in the last 6 months. Other inclusion criteria were having an Adult ADHD Investigator Symptom Rating Scale (AISRS) total score ≥26 and CGI-Severity of Illness (CGI-S) score ≥4 at baseline, BMI 18 to 35 kg/m², and being medically healthy.
• Exclusion criteria included having treatment-resistant ADHD, a current diagnosis of any psychiatric disorder other than ADHD, or a history of schizophrenia, schizoaffective disorder, BD, autism, obsessive-compulsive disorder, personality disorder, or posttraumatic stress disorder. Individuals with any significant neurologic disorder, heart condition, arrhythmia, clinically relevant vital sign abnormality, or systemic illness were excluded, as were those with a history (within the past year) or current diagnosis of substance use disorder or a positive drug screen for a drug of abuse. Those with an allergic reaction or intolerance to viloxazine or were breastfeeding, pregnant, or refused to be abstinent or practice birth control were excluded.
• The dosage of viloxazine ER ranged from 200 to 600 mg/d for 6 weeks. This was titrated based on symptom response and adverse effects.
• All individuals received 2 capsules once a day for Week 1 and Week 2. During Week 1 and Week 2, participants in the viloxazine ER group received 200 mg (1 viloxazine ER capsule and 1 placebo capsule) and 400 mg (2 viloxazine ER capsules) of the medication, respectively. Two placebo pills were administered to those in the placebo group. From Week 3 to Week 6, the dose could be titrated or tapered at the investigator’s discretion. Compliance was assessed by comparing the number of pills dispensed vs returned.
• The primary outcome was a change in AISRS score from baselines to Week 6.
• The key secondary outcome was the change in CGI-S score from baseline to Week 6. Scores on the AISRS inattention and hyperactive/impulsivity subscales, Behavioral Regulation Index, Metacognition Index, Behavior Rating Inventory of Executive Function–Adult Version (BRIEF-A), and Generalized Anxiety Disorder-7 item scale (GAD-7) were also evaluated. Also, the rates of 30% and 50% responders on the AISRS (defined as ≥30% or ≥50% reduction from baseline in AISRS total score, respectively), CGI-S scores, and CGI-Improvement (CGI-I) scores were examined.

Outcomes

• Based on change in AISRS total scores, patients who received viloxazine ER had significantly greater improvement in their ADHD symptoms than those taking placebo (P = .0040). Patients in the viloxazine ER group had significantly greater improvement in AISRS hyperactive/impulsive (P = .0380) and inattentive symptoms (P = .0015).
• The decrease in CGI-S score was also significantly greater in the viloxazine ER group than in the placebo group (P = .0023). The viloxazine ER group also had significantly greater improvement in executive function as assessed by the BRIEF-A (P = .0468). The difference in GAD-7 scores between the viloxazine ER group and the placebo group was not significant.
• The viloxazine ER group had a greater AISRS 30% response rate than the placebo group (P = .0395). There were no significant differences between groups in AISRS 50% responder rate or CGI-I responder rate.
• Adverse effects related to viloxazine and occurring in ≥5% of participants included insomnia (14.8%), fatigue (11.6%), nausea, decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). The discontinuation rate was 9.0% in the viloxazine ER group vs 4.9% in the placebo group.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Compared to placebo, patients treated with viloxazine ER had significantly greater improvements in ADHD symptoms, including both hyperactive/impulsive and inattentive components as well as executive function.
• The viloxazine ER group had a significantly higher AISRS 30% response rate than the placebo group, but there were no significant differences in anxiety symptoms or other measures of response.
• Viloxazine ER was well tolerated and safe.
• Limitations: There was a reduced power to detect differences in treatment due to participants dropping out or discontinuing treatment, a lack of interrater reliability data, and a lack of patient-reported outcome or satisfaction data.

3. Kis B, Lücke C, Abdel-Hamid M, et al. Safety profile of methylphenidate under long-term treatment in adult ADHD patients - results of the COMPAS study. Pharmacopsychiatry. 2020;53(6):263-271. doi:10.1055/a-1207-9851

Kis et al¹¹ analyzed the safety results of COMPAS.¹⁵ Details of this trial, including interventions and inclusion/exclusion criteria, are described in the description of Lam et al.⁹

Study design

• Researchers compared the rate of adverse events (AEs) among 205 patients who received ≥1 dose of methylphenidate with 209 patients who received placebo.
• AEs were documented and analyzed on an “as received” basis during Week 0 to Week 52. Electrocardiogram (ECG) data were recorded at baseline and Week 24. Vital signs were monitored at baseline, every week for the first 12 weeks, then every 4 weeks for the next 52 weeks. Body weight was assessed at Week 6, Week 12, Week 20, Week 28, Week 40, and Week 52. A 12-lead ECG was obtained at baseline and Week 24.
• The sample size was assessed to have 80% power to detect group differences in AEs.

Outcomes

• Overall, 96% of participants in the methylphenidate group and 88% of participants in the placebo group experienced at least 1 AE (difference 8.1%; 95% CI, 2.9% to 13.5%).
• AEs that occurred more frequently with methylphenidate compared to placebo were decreased appetite (22% vs 3.8%); dry mouth (15% vs 4.8%); palpitations (13% vs 3.3%); gastrointestinal (GI) infection (11% vs 4.8%); agitation (11% vs 3.3%); restlessness (10% vs 2.9%); hyperhidrosis, tachycardia, and weight decrease (all 6.3% vs 1.9%); depressive symptoms and influenza (both 4.9% vs 1.0%); and acute tonsillitis (4.4% vs 0.5%). Serious AEs were reported by 7.3% of patients in the methylphenidate group and 4.3% of those in the placebo group, with no difference in frequency (difference 3.0%; 95% CI, 1.6% to 7.9%). The most severe AEs were aggression, depression, somnambulism, and suicidal ideation in the methylphenidate group and car accidents, epicondylitis, and a fall in the placebo group.
• There were no significant differences in AEs between the GPT and CM groups.
• The treatment combinations that included methylphenidate had higher rates of patients experiencing at least 1 AE (CM/methylphenidate 97%, GPT/methylphenidate 96%, CM/placebo 92%, GPT/placebo 84%).
• Overall, 8.8% of patients in the methylphenidate group and 4.8% in the placebo group stopped their medication treatment because of an AE (difference 4.0%; 95% CI, 0.9% to 9.1%). At least 1 dose decrease, increase, or discontinuation was made after an AE in 42% of participants in the placebo group and 69% of those in the methylphenidate group.
• There were no significant differences in clinically pertinent ECG abnormalities between methylphenidate and placebo therapy.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• AEs were more common in the methylphenidate groups compared to placebo, but there was no significant differences for severe AEs. In the long-term, methylphenidate treatment was well tolerated and relatively safe.
• Limitations: The sample size may have been too small to detect uncommon AEs, all AEs had to be reported and may not have been caused by the treatment, and the original study’s main outcome was efficacy, not safety, which makes this an exploratory analysis of AEs.

4. Cutler AJ, Childress AC, Pardo A, et al. Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438

Once-daily dosing of stimulants, which are commonly used to manage adult ADHD,¹⁶ can be beneficial because many patients have schedules that limit taking medication multiple times a day. Cutler et al¹² looked at the efficacy and safety of amphetamine extended-release tablet (AMPH ER TAB), which is a 3.2:1 mixture of d- and l-amphetamine released by the LiquiXR drug delivery system. This technology allows for a continuous release following an initial quick onset of action.

Study design

• This parallel-study, double-blind study evaluated adults age 18 to 60 who had a diagnosis of ADHD according to DSM-5 criteria and the Adult ADHD Clinical Diagnostic Scale, normal-range IQ, AISRS score ≥26, and baseline CGI-S score ≥4.
• Women were not lactating or pregnant during the study.
• Exclusion criteria included a history of mental illnesses; chronic medical conditions; clinically significant abnormal ECG or cardiac findings on exam; renal or liver disease; family history of sudden death; significant vital sign findings; uncontrolled hypertension or a resting systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg; recent history of or current alcohol or substance use disorder; use of atomoxetine, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days of study or the use of other stimulant medications within 1 week of screening; use of GI acidifying agents or urinary acidifying agents within 3 days of screening; answering “yes” to questions 4 or 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale within 2 years prior to the study; taking another investigational medication within 30 days of screening; allergic to amphetamine or components of the study drug, and a lack of prior response to amphetamine.
• Patients were randomized to receive AMPH ER TAB (n = 65) or placebo (n = 65), taken before 10 am. Participants started at 5 mg/d of the drug/placebo and then entered a 5-week titration period in which the medication was increased by 5 mg/d each week until reaching 20 mg/d, and then continued 20 mg/d for 2 weeks.
• The primary outcome was the mean Permanent Product Measure of Performance Total (PERMP-T) score averaged across all time points (0.5-, 1-, 2-, 4-, 8-, 10-, 12-, 13-, and 14-hours postdose) at Visit 5.
• Participants underwent AISRS, CGI-S, and safety evaluations at baseline and at the 5 visits at the end of each treatment week.

Outcomes

• Analyses were completed on participants who received ≥1 dose of the medication and who had ≥1 PERMP-T score at Visit 5.
• Predose PERMP-T scores were similar between the AMPH ER TAB group (259.5) and placebo group (260). The mean postdose PERMP-T score in the AMPH ER TAB group (302.8) was significantly higher (P = .0043) than the placebo group (279.6).
• The PERMP-T scores were significantly different at 0.5-, 1-, 2-, 4-, 8-, and 13-hours postdose but not at 10-, 12-, and 14-hours postdose. The first Visit 5 time point at which the difference between groups was statistically different was at 0.5 hours postdose (P = .01), and the last significant time point was 13 hours (P = .006).
• The improvement in CGI-S scores was significantly greater in the AMPH ER TAB group than the placebo group. The improvement in AISRS scores was significantly greater in the AMPH ER TAB group at Visit 3, Visit 4, and Visit 5. More participants in the AMPH ER TAB group had AEs compared to the placebo group (90% vs 60%). The most common AEs (frequency ≥5% and occurring more in the intervention arm) were decreased appetite, insomnia, dry mouth, irritability, headache, anxiety, nausea, dizziness, and tachycardia.
• The AMPH ER TAB group had nonclinically significant increases in SBP (116.8 to 120.7 mmHg), DBP (74.1 to 77.1 mmHg), and heart rate (73.0 to 81.9 bpm) at Visit 5 compared to baseline.
• No serious AEs occurred. Three participants in the AMPH ER TAB group experienced AEs (increased blood pressure, CNS stimulation, and anxiety) that led them to discontinue the study.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• AMPH ER TAB reduced symptoms in adults with ADHD as assessed by improvement in PERMP-T scores.
• The safety and tolerability profile of AMPH ER TAB were comparable to other stimulants, with expected rises in blood pressure and heart rate.
• Limitations: Patients were required to be titrated to 20 mg/d of AMPH ER TAB, instead of following a flexible titration based on an individual’s response. Some participants may have had greater improvement at a higher or lower dose. This study did not compare AMPH ER TAB to other stimulants. The 5-week duration of this study limited the ability to evaluate long-term efficacy and tolerability. Patients with a wide range of psychiatric or medical comorbidities were excluded.

5. Iwanami A, Saito K, Fujiwara M, et al. Efficacy and safety of guanfacine extended-release in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2020;81(3):19m12979. doi:10.4088/JCP.19m12979

Guanfacine extended-release (GXR) is a selective alpha 2A-adrenergic receptor agonist approved for treating ADHD in children and adolescents.¹⁷ Iwanami et al¹³ evaluated the efficacy and safety of GXR for adults.

Study design

• This randomized, double-blinded, placebo-controlled trial enrolled Japanese adults age ≥18 who were diagnosed with ADHD according to DSM-5 criteria and scored ≥24 on the ADHD-Rating Scale IV (ADHD-RS-IV) and ≥4 on CGI- I.
• Exclusion criteria included having anxiety, depression, substance use disorder, tic disorder, BD, personality disorder, schizophrenia, or intellectual disability; a moderate or severe psychiatric disorder requiring treatment other than counseling; seizures; increased risk for suicide; a history of cardio­vascular disease, including prolonged QTc/abnormal ECG/abnormal labs, orthostatic hypotension, or continuous bradycardia; or taking medications that affect blood pressure or heart rate.
• Overall, 101 participants were randomized to the GXR group and 100 to the placebo group. Approximately two-thirds of the study population was male. Patients received GXR or placebo once daily at approximately the same time.
• There were 5 phases to the trial. The screening period occurred over 1 to 4 weeks. Part 1 of the treatment period consisted of 5 weeks of medication optimization. Participants were started on GXR 2 mg/d and were required to be receiving a minimum dose of 4 mg/d starting at Week 3. Clinicians were allowed to increase the dose 1 mg/d per week starting at Week 4 based on clinical response to a maximum dosage of 6 mg/d. Part 2 of the treatment period consisted of 5 weeks of maintenance at 4 to 6 mg/d. The tapering period to 2 mg/d occurred over 2 weeks. The follow-up period lasted 1 week.
• Efficacy measurements included the Japanese version of the ADHD-RS-IV and translations of the English-language CAARS, CGI-I, and CGI-S. Participant-reported measures included the Patient Global Impression-Improvement scale (PGI-I), Adult ADHD Quality of Life Questionnaire (AAQoL), and BRIEF-A.
• The primary outcome was the difference in ADHD-RS-IV total score from baseline to the end of the maintenance period (Week 10).
• Safety assessments were completed at Week 5 (end of dose optimization period), Week 10 (end of dose maintenance period), and Week 12 (tapering period).

Outcomes

• The average GXR dose during the maintenance period was 5.07 mg/d.
• Compared to the placebo group, the GXR group had more patients age <30 (47% vs 39%) and fewer patients age ≥40 (17% vs 27%). Baseline ADHD-RS-IV scores in both groups were comparable. At baseline, 51% in the GXR group had a combined inattentive/hyperactive-impulsive presentation and 47% had a predominately inattention presentation, with similar characteristics in the placebo group (49% combined, 49% inattention).
• At Week 10, the least squares mean change from baseline on the ADHD-RS-IV total score was significantly greater in the GXR group than in the placebo group (-11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005), with an effect size of 0.52. There was a greater decrease in the ADHD-RS-IV scores starting at Week 4 and continuing to Week 10 (P < .005).
• There were also significant differences favoring GXR on the ADHD-RS-IV hyperactivity-impulsivity subscale score (P = .0021) and ADHD-RS-IV inattention subscale score (P = .0032).
• There were significant differences in the CAARS total ADHD score (P = .0029) and BRIEF-A scores on the inhibit (P = .0173), initiate (P = .0406), plan/organize (P = .174), and global executive composite index (P = .0404) scales. There was no significant difference in the total AAQoL score (P = .0691), but there was a significant improvement in the AAQoL life productivity subscore (P = .0072).
• At Week 10, there were also significant improvements in the CGI-I scores (P = .0007) and PGI-I scores (P = .0283). The CGI-S scores were similar at all time points.
• Overall, 81.2% of GXR patients reported AEs compared to 62% in the placebo group. There was 1 serious treatment-emergent AE (a suicide attempt) that the authors concluded was unrelated to the study drug. No deaths occurred. The most common AEs (incidence ≥10% in either group) included somnolence, thirst, nasopharyngitis (occurring more in the placebo group), blood pressure decrease, postural dizziness, and constipation. The main AEs leading to discontinuation were somnolence and blood pressure decrease. Overall, 19.8% of patients receiving GXR discontinued treatment due to AEs, compared to 3% in the placebo group.
• Heart rate, blood pressure, and QTc (corrected by the Bazett formula) were decreased in the GXR group at Week 10 while QT and RR intervals increased, and most returned to normal by Week 12.

Continue to: Conclusions/limitations

 

 

Conclusions/limitations

• Compared to placebo, GXR monotherapy resulted in clinical improvement in ADHD symptoms, with a moderate effect size.
• The most common AEs were mild to moderate and congruent with known adverse effects of guanfacine. Sedation effects mostly transpired within the first week of medication administration and were transient.
• Limitations: The findings might not be generalizable to non-Japanese patients. The duration of the study was short. Patients with a wide range of psychiatric and medical comorbidities were excluded. Two-thirds of the participants were male, and there was a disparity in participant age in the GXR and placebo groups.

6. Reimherr FW, Gift TE, Steans TA, et al. The use of brexpiprazole combined with a stimulant in adults with treatment-resistant attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2022;42(5):445-453. doi:10.1097/JCP.0000000000001592

While stimulants are a mainstay ADHD treatment, some patients have a partial response or do not respond to amphetamines or methylphenidate. Reimherr et el¹⁴ assessed the efficacy and safety of adding brexpiprazole (BXP) to a stimulant.

Study design

• This randomized, double-blinded, placebo-controlled trial recruited 559 stimulant-naive patients and 174 patients who had not responded to previous stimulant therapy.
• Participants were adults age 18 to 55 with a primary diagnosis of ADHD according to DSM-IV-TR criteria and the Conners Adult ADHD Diagnostic Interview. Other inclusion criteria were having a CAARS score ≥29 and a CGI-S score ≥4.
• Exclusion criteria included being at risk for suicide; having current substance abuse or positive alcohol/drug screens; a history of good response to prestudy treatment; a clinically significant medical condition; fasting blood glucose >200 mg/dL or hemoglobin A1C >7%; and hospitalization in past 12 months from a diabetic complication, uncontrolled hypertension, ischemic heart disease, or epilepsy. Further exclusion criteria included a history of psychosis, current MDD or BD, current panic disorder, uncontrolled comorbid psychiatric condition, or clinically significant personality disorder. Investigators excluded any patient with severe DSM-IV axis I or II disorders or abnormal/psychopathological behaviors.
• The trial consisted of 3 segments. Part 1 was screening. If the patient was currently receiving a stimulant but not fully responding, the medication was discontinued for at least 5 half-lives.
• Part 2 (5 weeks) involved administering a stimulant plus a single-blind placebo (597 patients completed this phase). The stimulant was chosen by the investigator, who had the option of using 1 of 2 amphetamine derivatives (mixed amphetamine salts capsules or lisdexamfetamine dimesylate capsules) or 1 of 2 methylphenidate derivatives (methylphenidate hydrochloride ER tabs or dexmethylphenidate HCl ER capsules). If a patient did not respond to a particular stimulant prior to the study, they were given a different stimulant from the list. Patients continued the same stimulant throughout the trial. Patients were monitored for a response, defined as a ≥30% decrease in CAARS score or a CAARS score <24, or a CGI-I score of 1 or 2 at Week 5. Patients who did not show this improvement were categorized as open-label nonresponders.
• Part 3 (6 weeks) involved administering a stimulant plus double-blind BXP vs placebo (stimulant-naive n = 167, stimulant nonresponders n = 68). Nonresponders continued the stimulant (at the same dose reached at the end of Part 2) and added either BXP (n = 155) or continued placebo (n = 80). Patients who responded in Part 2 were continued on the stimulant plus placebo and were not randomized. Patients were started on BXP 0.25 mg/d, and the medication could be titrated to 2 mg/d during the following 3 weeks, depending on the benefit vs AE profile. After the third week, the dose could be decreased but not increased.
• The primary outcome was a change in CAARS score. Secondary measurements included the CGI-S, Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), Montgomery-Åsberg Depression Rating Scale (MADRS), and BDI.

Outcomes

• Stimulant-naive patients were equally divided among the 4 stimulant groups, and previous nonresponders who continued to not respond in Part 2 were more likely to be given methylphenidate HCl or lisdexamfetamine dimesylate.
• Patients with a history of nonresponse had less response to stimulants in Part 2 compared to stimulant-naive patients, as seen by 27% (n = 167) of stimulant-naive patients entering Part 3 compared to 39% of prior nonresponders (n = 68; P = .0249).
• ADHD improvement with BXP appeared to be greater among pretrial nonresponders.
• For stimulant nonresponders before and during the study, at the end of the double-blind endpoint (Part 3; Week 11), WRAADDS total score was significantly improved in the BXP group compared to the placebo group (P = .013; d = 0.74), with most beneficial effects seen in the hyperactivity/restlessness, emotional dysregulation factor, and impulsivity categories.
• For stimulant nonresponders before and during the study, there was no significant difference at the end of Week 11 on the CAARS (P = .64), MADRS (P = .37), or BDI (P = .73). There was a trend toward significance on the CAARS subscale for hyperactive/impulsive (P = .09).
• For prestudy stimulant-naive patients who did not respond to stimulants in Part 2 and were randomized in Part 3, there was not a significant difference between BXP and placebo at Week 11 as assessed on WRAADDS, CAARS, MADRS, or BDI.
• As assessed on WRAADDS, 50% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.334). Under the emotional dysregulation factor category of the WRAADDS, 64% in the BXP group had a response compared to 41% in the placebo group (Fisher exact = 0.064). The attention factor category showed a 40% improvement in the BXP group compared to 32% in the placebo group (Fisher exact = 0.344).
• There were 2 serious AEs in the BXP group (gall bladder inflammation and diarrhea) and 2 in the placebo group (pneumonia and urinary tract infection). There was no statistically significant difference between groups with regards to common AEs (ie, fatigue, heartburn/nausea/stomachache, weight loss), although there was a trend to significant for insomnia in the BXP group (P = .083).

Conclusions/limitations

• Stimulant-naive patients experienced no improvement with adjunctive BXP.
• For prior stimulant nonresponders, there was no significant difference between BXP vs placebo on the primary outcome of the CAARS score, but there was an improvement as observed by assessment with the WRAADDS.
• The largest change in the WRAADDS occurred in the emotional dysregulation factor compared to the attention factor.
• BXP appeared to be well tolerated.
• Limitations: The WRAADDS was administered without the patients’ significant other/collateral. Raters were not trained in the use of the WRAADDS. Patients with a wide range of psychiatric and medical comorbidities were excluded. Fewer patients were recruited in the prior stimulant nonresponder group.

Bottom Line

Recent randomized controlled trials suggest that methylphenidate, amphetamine extended-release, viloxazine extended-release, and guanfacine extended-release improved symptoms of adult attention-deficit/hyperactivity disorder (ADHD). There were no improvements in ADHD symptoms with adjunctive brexpiprazole.

Related Resources

• Parikh AR, Baker SA. Adult ADHD: pharmacologic treatment in the DSM-5 era. Current Psychiatry. 2016;15(10):18-25.
• Akbar HN. Why we should be scrutinizing the rising prevalence of adult ADHD. Current Psychiatry. 2022; 21(7):e1-e2. doi:10.12788/cp.0268

Drug Brand Names

Amantadine • Gocovri
Amphetamine extended-release tablet • Dyanavel XR
Atomoxetine • Strattera
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Dexmethylphenidate • Focalin
Fluoxetine • Prozac
Guanfacine extended- release • Intuniv
Lisdexamfetamine • Vyvanse
Methylphenidate • Concerta, Methylin
Theophylline • Elixophyllin
Viloxazine • Qelbree