Introduction
Attention-deficit and hyperactivity disorder (ADHD) is characterized by symptoms such as inattention, disorganization, hyperactivity/restlessness, impulsivity, and emotional dysregulation.1,2) Approximately 30%–60 % of patients with ADHD in childhood have symptoms of inattention and poor concentration that extend into adulthood.3–5) Adult ADHD presents with different or modified symptomology compared to childhood ADHD. For example, adult ADHD presents with less hyperactivity, which is replaced with restlessness.6) Furthermore, adult ADHD patients often have high-risk comorbid psychiatric disorders, such as substance use disorders7) and suicidal ideation.8) For pharmacological treatments for adult ADHD, stimulant medications, including methylphenidate, dexmethylphenidate, and amphetamines, have been approved,9–11) while cognitive behavioral therapies can be applied to adult ADHD as a non-pharmacological intervention.11) Researchers have reported case series of successful neurofeedback12) and brief cognitive behavioral therapy13) strategies in patients with adult ADHD. In addition, acupuncture treatment, an alternative therapy, has been shown to improve working memory14) and cognitive task performance15) in college students.
In recent times, there have been an increasing number of clinical studies regarding East Asian herbal medicine for the treatment of ADHD in children. Ningdong granule, a Chinese medicine preparation, which includes Gastrodiae rhizoma, Ophiopogonis radix, and Paeoniae alba radix, was reported to be more effective and safer for children with ADHD than the standard pharmacologic treatment with methylphenidate in a randomized controlled trial.16,17) In addition, administration of the Chinese herbal medicine formula named “ind-anchoring granules,” which contains Poria cocos, Acori graminei rhizoma, Alpiniae oxyphyllae fructus, Polygalae radix, Tritici fructus levis, and Zizyphi fructus, showed potential therapeutic effects in the treatment of children with ADHD.18) However, to the best of our knowledge, there are limited reports on the use of herbal medicines for the treatment of adult ADHD. We present here the first chart review of treatment with Korean medicine treatments including herbal medicine for adults with ADHD. This chart review aimed to explore which herbs and formulae are used for treatment of adult ADHD. In addition, we aimed to provide objective results of various cognitive tasks before and after herbal medicine treatment.
Method
1. Case selection
A retrospective chart review was performed in a Korean medicine clinic (Seoul, Republic of Korea) specializing in ADHD and tic disorders. From November 2015 to July 2019, appropriate cases were selected based on the following criteria: 1) male and female patients aged 20 to 30 years who were diagnosed with adult ADHD, 2) patients who had been administered herbal medicine for more than 3 months, and 3) patients with cognitive testing results before and after the treatment. The Institutional Review Board of the Korean Institute of Oriental Medicine approved this study (KIOM IRB No. I-2101/001-003). All patients provided written consent for their medical records to be used anonymously for academic purposes.
2. Clinical profile
A total of eight cases with adult ADHD were included in this retrospective chart review, according to the criteria described above. The clinical profiles of the patients are presented in Table 1. The median age of the patients was 25 years, ranging from 20 to 27 years. Four female and four male patients were included in the study. Among the eight patients, two patients were diagnosed with a combined type of ADHD, and the other six patients were diagnosed with a predominantly inattentive type ADHD. Two patients were using methylphenidate for the treatment of ADHD. Patients’ chief complaints were lack of concentration, poor attention, difficulty in adaptation to work, poor learning ability, poor social skills, difficulty concentrating on conversation, and difficulty in controlling emotions such as depression and anger.
3. Clinical findings
1) Computerized comprehensive attention test (CAT)
A computerized comprehensive attention test (CAT) is administered to assess the inattention and hyperactivity of adults with ADHD. This test was developed by the Korean Academy of Child and Adolescent Psychiatry,19) and standardized data from the test were collected within a representative subset of the general Korean population, including participants in their 20s, 30s, and 40s.20) The test consists of six attention tests: a visual selective attention test, an auditory selective attention test, a flanker test (FT), a sustained attention test (SAT), a divided attention test (DAT), and a working memory test (WMT). For adults with suspected ADHD, four tests for CAT were administered: SAT, FT, DAT, and WMT. In SAT, DAT, and FT, patients were instructed to press the button when a target stimulus was presented. The following measures were assessed: frequency of commission error (CE) – an inappropriate response to the target stimulus, indicative of poor inhibition control; frequency of omission error (OE) – failure to respond to the target stimulus, indicative of poor vigilance; mean reaction time (RT) – indicative of latency of the response; and the standard deviation of the mean reaction time (RTsd) – indicative of the consistency of the test taker’ attention.21,22) In addition, the attention quotient (AQ) was calculated under the assumption that the mean score was 100, and the standard deviation of the score was 15, based on age-specific data from standardized tests.
The baseline CAT results are presented in Table 2. No patient showed low scores in CE. The OE of SAT, RT of DAT, FCR, and FSN of WMT were the items for which more than three patients showed low scores (less than the expected mean score of their age minus 1 standard deviation).
2) Adult self-report
The Achenbach ASR test23,24) was measured at baseline. ASR is composed of eight sub-domains: anxiety/depression, withdrawing, somatic complaints, thought problems, attention problems, aggressive behavior, rule-breaking behavior, and intrusive thoughts. A T score higher than 64 indicates a clinically relevant high score in theses sub-domains. Five patients completed the Achenbach ASR23,24) at the baseline assessment. The median T scores for anxiety/depression, withdrawal, attention problems, aggressive behavior, and rule-breaking behavior were higher than 64. The baseline ASR results are listed in Table S1.
3) Resting state electroencephalography (EEG)
Resting state electroencephalography (EEG) was measured using Neuronisc 32 (Intermend, Seoul, Korea), through eight channels placed on the head, according to guidelines from the international 10/20 system.25) Measurements were conducted for 5 minutes while participants wat upright with eyes closed in a comfortable position. Decreased alpha (8–13 Hz) and increased theta (4–8 Hz) power in the frontal lobe were observed in five patients with predominantly inattentive type ADHD, whereas increased alpha (8–13 Hz) or beta (13–30 Hz) power were observed in the other three combined subtypes.
4. Diagnostic Assessment
Adult ADHD was diagnosed according to DSM 5 diagnostic criteria.9,26) Patients were carefully interviewed with regard to childhood history of ADHD and the current presence of clinical symptoms in the inattentive and hyperactive-impulsive domains. Additionally, the results of CAT, ASR, and resting EEG testing were comprehensively considered.
5. Therapeutic intervention
1) Herbal medicine
Individualized herbal medicine formulas were prescribed to diagnosed adult ADHD patients. The names of the prescribed formulas and target symptoms are presented in Table 3. Detailed information on the composition of the prescribed formula is presented in Table S2. Acori graminei rhizoma was the most frequently prescribed herb, commonly included in formulas for all eight patients with adult ADHD, followed by Polygalae radix, which was prescribed for seven patients. Angelicae gigantis radix and Bupleuri radix were prescribed for six patients, and Ephedrae herba and Gardeniae fructus were prescribed for five patients. The herbal medicine decoction (120 cc) was administered twice a day for 5.4 ± 3.5 months for all patients. The treatment duration ranged from 3 to 12 months.
The herbal medicine formula for each patient was decided based on certain criteria and symptoms. Chongmyung-tang (Cong ming tang in Chinese), composed of Acori graminei rhizoma, Polygalae radix, and Poria sclerotium, was used to alleviate inattention. Patients with anxiety and depression were prescribed Guipi decoction (Guipi Tang in Chinese), including the herbs Angelicae gigantis radix and Longan arillus. Patients with anger, irritation, and aggressive behaviors were prescribed Danchisoyo-san (modified xiaoyao san in Chinese), including the herbs Gardeniae fructus and Moutan radicis cortex. Patients with decreased energy, poor appetite, and indigestion were prescribed Yikwiseungyang-tang (Yiwei Shengyang Tang in Chinese), including the herbs Astragali radix and Citri unshius pericarpium. Yukmijihwang-tang (Liuwei Dihuang Tang in Chinese) was prescribed to improve cognitive ability, which including the herbs Rehmanniae Radaix Preparata and Corni Fructus.
2) Acupuncture
Acupuncture was applied to all patients. Each patient completed twenty-two sessions of acupuncture treatment during the first three months. Four patients underwent an additional twenty-two sessions over the following three months. Acupuncture treatment was applied bilaterally for 20 minutes at the following acupoints: KI3, KI7, and KI10. Sterilized disposable acupuncture needles (0.25mm in diameter and 30mm length) were inserted into the acupoints using an acupuncture assistant (AcuPro, NeoDr Inc., Korea).
3) Neurofeedback
Neurofeedback was administered for the same number of sessions as acupuncture treatment. During each visit, patients received both acupuncture and neurofeedback treatment. Neurofeedback was conducted using a rewarding frequency band generally set to 12 to 15 Hz (15 to 18 Hz in two patients), using the ProComp Infiniti encoder (Thought Technology Ltd., Canada). Electrodes were attached to the CZ (four patients), C3 (two patients), C4 (one patient), or T3 (one patient) during the neurofeedback training. Respiratory biofeedback, computerized cognitive training, and auditory perception training were also applied to some patients. All neurofeedback and biofeedback sessions were conducted by therapists who completed biofeedback trainer certification.
Result
1. Follow-up and outcomes
1) Computerized comprehensive attention test (CAT)
After completion of the herbal medicine administration, the CAT was measured for the post-treatment assessment. The CAT test domains were measured again at the post-treatment assessment for cases showing a low AQ score (under 85). To assess treatment effectiveness, CAT results before and after treatment were considered. In addition, the number of patients whose AQ score changed from abnormal (AQ score < 85) to the normal range is presented in the results.
CAT results before and after treatment are shown in Table 4. After treatment, all patients showed improved scores for at least one CAT item. Among the four patients with an increased number of OEs in attention tasks, three patients showed improvement and one patient showed no change. Among the four patients with delayed RT, only two showed improvements to the normal range. FCR and FSN in WMT improved in all five patients after treatment. The plots of the CAT scores for individual patients before and after treatment are presented in Figure 1 and 2. There were some missing data because the post-treatment test was only measured in cases with a low baseline AQ score (under 85). In the post-treatment assessment, SAT, DAT, and WMT were measured in six, three, and five patients, respectively. It seems that the decreased RT of the SAT and DAT is difficult to improve with treatment (Figure 1). In contrast, FCR and the FSN of WMT gradually improved to the normal range after treatment (Figure 2).
2) Adverse events
For safety assessment, adverse events that occurred in patients during the treatment period were carefully obtained from the chart. Mild gastrointestinal adverse events have been reported in some patients after administration of herbal medicine. Two patients reported loose stools, and one patient reported indigestion. These gastrointestinal events were evaluated as mild and were probably related to the intervention.
2. Patient perspective
Qualitative information about the patient perspectives was collected through chart reviews. Improvements in ability, skills, and performance at work and school have been commonly reported. One patient said that she made many mistakes despite hard efforts before the treatment, such as with regard to taking notes, but the frequency of mistakes gradually decreased during the treatment period. Another patient said that it was difficult to control various tasks before treatment, but their ability to organize and handle various tasks improved after the treatment. Another patient said that distractions and inattention made it difficult to read books or documents before the treatment, but after treatment, it was possible to read with concentration. In addition, alleviation of symptoms in emotional areas has been reported after treatment, such as relaxation of the mind, and a reduction in anxiety and depressive symptoms. Improvements in psychosomatic symptoms, such as headache, have also been reported.
Discussion
1. Korean medicine treatments for attention and working memory
Inattention is a common symptom in patients with ADHD, presenting as a lack of attention to detail and difficulty in sustaining attention.26,27) Therefore, patients with ADHD show poor performance in tasks requiring sustained efforts.28) In this study, some patients frequently made errors in the SAT, which measures sustained attention; this behavior improved overall post treatment. Working memory plays an important role in cognition,29) and deficits in WMTs commonly appear in adults with ADHD.30) In this study, most patients had low scores on the working memory test at the baseline assessment; these scores were recovered to the normal range after treatment. Several patients reported improvements in their abilities at work and school, which may be related to improvements in their working memory capacity.
2. Potential of herbal medicine for treating adult ADHD
Despite thorough literature review, we found no published studies investigating herbal medicine specifically for adult ADHD. In this chart review, Acori graminei rhizoma, Polygalae Radix, Angelicae Gigantis Radix, and Bupleuri radix were frequently used herbs for treating adult ADHD. Acori graminei rhizome and Polygalae radix are included in the herbal medicine prescription Chongmyung-tang.31) Chongmyung-tang has shown effects on improving memory in various memory impairment in vivo models.31,32) Herbs included in Guibi-tang (Angelicae gigantis radix, Longan arillus) were also frequently prescribed. Guibi-tang is a recommended formula for the predominantly inattentive type of ADHD.17) There were more inattentive type ADHD cases than combined or hyperactive type ADHD cases in adults with ADHD in our study. Modified type of Guibi-tang have also shown effects on cognitive function in patients with mild cognitive impairment33) and have alleviated depressive-like behaviors in chronic unpredictable mild stress model.34) Herbs included in Yukmijihwang-tang were used for a few patients; this is the recommended formula for the combined type of ADHD.17) Yukmijihwang-tang is another memory-enhancing herbal formula.35) In summary, Chongmyung-tang, Guibi-tang, and Yukmijihwang-tang are formulas with reported positive effects on cognitive functions. A systematic review of East Asian herbal medicine for ADHD in children identified Acori graminei rhizoma, Polygalae radix, Fossilia ossis mastodi, Rehmanniae radix preparata, and testudinis chinemis plastrum et carapax as the five most frequently prescribed herbs.36) In a survey for Korean medicine doctors, over 10% of respondents reported using ondam-tang, eokgan-san, sihogayonggolmoryeo-tang, guibi-tang for treating ADHD in children and adolescents.37) Acori graminei rhizoma, Polygalae radix, Rehmanniae radix preparata, and Guibi-tang were also documented in our chart review.
3. Potential of acupuncture for treating adult ADHD
A pilot randomized controlled trial enrolling 19 adults with ADHD found that acupuncture as an add-on to methylphenidate treatment showed a tendency toward greater improvement compared to the control group. The study used GV20, GV24, and EX-HN1 as basic acupoints, with ST36, SP6, LR3, and HT7 added based on pattern identification.38) In a case report of adult ADHD, 16 sessions of acupuncture over 8 weeks, combined with atomoxetine, improved core ADHD symptoms and decreased perceived stress. 39) The authors reported primarily using SP6 and LR3 according to Chinese medicine pattern diagnoses. In our retrospective chart review, KI3, KI7, and KI10 were used, which differed from the acupoints used in previous reports. A systematic review of acupuncture treatment for ADHD in children identified LR3, SP6, KI3, PC6, GV20, and GV24 as the six most commonly used acupoints.40) Several of these acupoints (LR3, SP6, KI3, GB20, and GV24) were also documented in previous adult ADHD studies and our chart review.
4. Limitation of this study
Our study has several limitations. First, limited ADHD-specific outcome measurements, such as the Adult ADHD Self-Report Scale (ASRS),41,42) were reported in this study. However, cognitive tests included in the CAT are also among the objective neuropsychological outcomes used for evaluating adult ADHD,30) and improvement in ADHD symptoms is highly related to improvement in attention tests.43,44) In this chart review, we provided CAT results before and after Korean medicine treatments. Adding ASRS to the assessment battery of adult ADHD would be valuable for further research and clinical observation. Second, this study is a chart review including a few case series, with data obtained before and after treatment, which has limitations in assessing the effectiveness and safety of Korean medicine treatments for adult ADHD. To evaluate the efficacy and safety of Korean medicine treatments for ADHD, a highly rigorous prospective clinical research with control groups, such as randomized controlled trials, is needed. Third, this chart review was based on a report by a Korean medicine clinic. To explore how Korean medicine clinics are currently approaching and managing adult ADHD patients, it is necessary to collect case series from various sites. Herbal medicine has been used to improve symptoms of adult ADHD patients in real clinical settings for several years in Korea, so there is a need to establish a related practice-based research network and collect case reports systematically.
Conclusion
This chart review is, to the best of our knowledge, the first report of Korean medicine treatments for adult ADHD. After administration of herbal medicine prescriptions, acupuncture, and neurofeedback for 3 to 12 months, attention and working memory measured by CAT were generally improved in patients with adult ADHD. In addition, we collected data on which herbal medicine formulas are prescribed and which concomitant therapies are applied in a Korean medicine clinic. This study is meaningful as basic data for further research.
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