Advances in drugs for attention deficit hyperactivity disorder (ADHD)

Attention Deficit Disorder with Hyperactivity (ADHD) is a heterogeneous, complex and chronic neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity, which can be observed as early as three years old To
.
Children and adults with ADHD exhibit inattention, hyperactivity, and impulsivity that are not commensurate with their age
.
They often find it difficult to maintain normal interpersonal relationships, and it is difficult for them to succeed in school, workplace, or other areas
.
The symptoms of ADHD in adults are very similar to those in children, manifested as restlessness, easy distraction, difficulty maintaining attention, impulsivity, and/or impatience
.
They often cannot tolerate pressure, which leads to greater emotional expression
.
"Diagnostic and Statistical Manual of Mental Disorders" Fifth Edition (DSM-5) classification system identified three main subtypes of ADHD: inattention performance, hyperactivity/impulsive performance and comprehensive performance
.
PART 0 1.
Genetic performance of ADHD In 2019, "Nature Genetics" published a genome-wide association meta-analysis in 20183 ADHD patients and 35191 controls, and determined the significance of more than the whole genome in 12 independent loci The variation of ADHD has discovered important new information about the potential biology of ADHD [1]
.
PART 0 2.
The epidemiology of ADHD The 2013 Global Burden of Disease (GBD) study reported nearly 40 million prevalent cases of attention deficit hyperactivity disorder, an increase of 13.
8% compared to the prevalence described in 1990, but age-standardized The prevalence rate dropped slightly (-0.
5%)
.
According to the latest published meta-analysis studies, it is estimated that the global prevalence of ADHD in children and adolescents is 5.
9-7.
1%, and that of adults is 2.
5-3.
4%
.
In addition, a recent meta-analysis showed that the average prevalence of children and adolescents is 7.
2%
.
Although many studies have shown that the prevalence of ADHD is on the rise, the authors of a meta-analysis of 135 epidemiological studies published between 1985 and 2012 believe that after adjusting for differences in the methods of these studies, in the past three decades The prevalence of the disease here remains unchanged
.
In a systematic review and meta-analysis of 67 studies involving 275,500 people, the comprehensive prevalence of ADHD among Chinese children and adolescents was estimated to be 6.
26%
.
In men of all ages, the incidence of ADHD is much higher, and boys are 4-9 times more likely to be diagnosed with ADHD than girls
.
However, this statistic may be misleading because girls are more likely to show inattention and therefore may be less likely to get treatment than boys
.
PART 0 3.
Listed drugs ADHD treatment drugs can be divided into central stimulants, norepinephrine reuptake inhibitors, and others, such as α2 adrenergic receptor agonists, according to their mechanism of action
.
It should be noted that the central stimulant methylphenidate hydrochloride belongs to the first category of psychotropic drugs
.
According to the "Regulations on the Administration of Narcotic Drugs and Psychotropic Drugs", the state implements a designated production system for narcotic drugs and psychoactive drugs; designated production enterprises shall have corresponding qualifications; enterprises engaged in the production of narcotic drugs and psychoactive drugs shall be approved by the local people of the province, autonomous region, and municipality directly under the Central Government.
Approved by the government drug regulatory agency
.
01 Central stimulant: In 1955, the US FDA approved Novartis's amphetamine derivative methylphenidate hydrochloride (Methylphenidate hydrochloride) to be marketed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy
.
In 2002, the FDA approved the sale of Dexmethylphenidate hydrochloride oral tablets, and in 2006 approved the sale of sustained-release capsules of Dexmethylphenidate hydrochloride. .
As a central nervous stimulant, methylphenidate works by blocking the reuptake of norepinephrine and dopamine by presynaptic neurons and increasing the release of these monoamines to the outer neuronal space
.
On March 2, 2021, a compound drug Serdexmethylphenidate/dexmethylphenidate (trade name Azstarys) developed by Kempharm was approved by the US FDA for the treatment of attention deficit disorder with hyperactivity
.
According to Yaodu data, the domestically marketed imported drug is Johnson & Johnson's methylphenidate hydrochloride sustained-release tablets (18 mg, 36 mg)
.
An injection made with generic methylphenidate One of Suzhou Pharmaceutical Co.
, Ltd.
and Tonghua Crane Pharmaceutical Resources Jen Pharmaceutical Co.
, Ltd.
and Suzhou methylphenidate hydrochloride tablets of Pharmaceutical Co.
, Ltd.
One
.
A 40-week randomized double-blind placebo-controlled multi-center clinical efficacy and safety study phase III trial of Novartis (NCT01259492) pointed out that the treatment failure rate (21.
3%) of the methylphenidate hydrochloride sustained-release capsule group within 6 months of validity Significantly lower than placebo (49.
6%), but the percentage of adverse reactions in the methylphenidate hydrochloride group was higher
.
Since the effectiveness of long-term use (more than 7 weeks) has not been systematically evaluated in controlled trials, doctors should periodically reassess the long-term effectiveness of the drug on individual patients
.
The drug has serious adverse reactions, weight loss during long-term treatment, growth inhibition, long-term abuse can lead to obvious tolerance and psychological dependence, and abnormal behaviors of varying degrees, children under six years of age are prohibited from using it
.
Yaodu data shows that Johnson & Johnson's methylphenidate hydrochloride (CONCERTA) has an annual growth rate of -3.
37% from 2017 to 2020. .
Novartis's Ritalin/Focalin hydrochloride (Ritalin/Focalin) has an annual growth rate of -8.
16% from 2011 to 2017.
The other central stimulant lysine amphetamine mesylate was approved by the US FDA on February 23, 2007 ( Trade name Vyvanse) for the treatment of ADHD; on March 26, 2019, it was approved by the PMDA of Japan's Agency for Pharmaceuticals and Medical Devices
.
On January 27, 2016, Neos' amphetamine sustained-release orally disintegrating tablet Amfetamine polistirex (trade name Adzenys xr-odt) was approved by the US FDA for the treatment of attention deficit disorder with hyperactivity
.
02 Norepinephrine reuptake inhibitor On November 26, 2002, the US FDA approved Eli Lilly’s selective norepinephrine reuptake inhibitor atomoxetine hydrochloride (Atomoxetine hydrochloride) oral capsules for the market, for treatment attention Force deficit/hyperactivity disorder
.
On May 12, 2006, NMPA approved its oral solution and capsule for domestic marketing
.
According to NMPA, the Tomoxetine Hydrochloride Capsules produced by Shandong Bainuo Pharmaceutical Co.
, Ltd.
, Tianfang Pharmaceutical Co.
, Ltd.
and Jiangsu Zhengda Fenghai Pharmaceutical Co.
, Ltd.
and Shandong Langnuo Pharmaceutical Co.
, Ltd.
(marketing license holder: Guizhou Yi The generic drug of Tomoxetine Hydrochloride Oral Solution from Bai Pharmaceutical Co.
, Ltd.
was approved for marketing
.
According to a randomized double-blind phase IV clinical trial of placebo and atomoxetine hydrochloride (NCT00190775, Eli Lilly), compared with placebo-treated patients, total ADHD symptoms were reduced by 25% in patients treated with atomoxetine
.
Data presented at the Conference of Child and Adolescent Psychiatrists in October 2006 showed that atomoxetine improved the symptoms of pediatric and adolescent patients with ADHD and ADHD plus dyslexia (ADHD+RD); ADHD group and ADHD+ Compared with the RD group, the improvement rates of ADHD symptoms at 16 weeks were 52% and 49.
2%, respectively
.
In May 2003, data from an adult clinical trial showed that in the 10-week acute phase, all indicators of the patients treated with atomoxetine were significantly improved compared with placebo; the ADHD symptom score of patients entering the extended phase was from baseline ( Acute phase) 34.
5±7.
3 decreased to 19.
2±11.
3
.
The American Psychiatric Association showed at a conference held in New Orleans, Los Angeles in 2001, that atomoxetine is as effective as methylphenidate
.
The most common adverse reactions shown in clinical trials in children and adolescents are nausea, vomiting, fatigue, loss of appetite, abdominal pain, and drowsiness
.
The most common adverse reactions shown in adult clinical trials are constipation, dry mouth, nausea, loss of appetite, dizziness, erectile dysfunction, and urinary retention
.
Compared with methylphenidate, atomoxetine hydrochloride has no drug dependence, but it can increase the risk of suicidal ideation in children or adolescents
.
According to Yaodu data, the annual growth rate of global sales of Tomoxetine hydrochloride from 2011 to 2016 was 6.
31%, but the global sales continued to decline since 2017, and it was only US$242.
5 million in 2019 (the highest point was US$854.
7 million in 2016)
.
Veroxazine hydrochloride (Viloxazine hydrochloride) is a norepinephrine reuptake inhibitor developed by Supernus Pharmaceuticals Inc.
Veroxazine hydrochloride (trade name QELBREE) was approved by the US FDA for attention on April 2, 2021.
Treatment of defects with hyperactivity
.
An interventional, parallel allocation, randomized phase III clinical trial (NCT03247517) to evaluate the efficacy and safety of two low-dose veloxacin hydrochloride in adolescents aged 12 to 17 years with ADHD
.
The ADHD-RS-V scores of patients treated with veroxaqin hydrochloride 200 mg and 400 mg at week 6 were -16.
0 points and -16.
5 points, respectively, compared with the changes in the placebo group
.
The magnitude of the efficacy of patients receiving 200 mg and 400 mg was 0.
47 and 0.
50, respectively
.
A randomized, open-label phase III clinical trial (NCT03247543) to evaluate the efficacy and safety of two doses of veroxaqin hydrochloride in children with ADHD from 6 to 11 years old
.
The results of the trial showed that the primary endpoints of patients treated with viloxacin 200 mg and 400 mg were -17.
6 and -17.
5 (placebo -11.
7), respectively
.
In the results of the phase IIb study, the magnitude of the effect for patients receiving 200 mg and 400 mg was 0.
46 and 0.
49, respectively
.
Both effective doses were well tolerated
.
However, it should be noted that in clinical trials, it was found that the incidence of suicidal thoughts and behaviors in children treated with veloxaqin hydrochloride was higher than that in children treated with placebo
.
03 Other Stepholidine is a dopamine receptor (DRD1, DRD2) antagonist
.
On January 1, 1995, the drug was approved by the National Medical Products Administration of China NMPA for the treatment of ADHD
.
At the same time, Hyperactivity Tourette's syndrome, migraine and headache have also been approved for marketing by NMPA
.
Guanfacine hydrochloride (Guanfacine hydrochloride) is an α2 adrenergic receptor agonist with preferential affinity for α2A receptors.
It was first marketed in 1981 for the treatment of hypertension
.
In 2009, the drug was approved to be marketed in the United States for the treatment of ADHD
.
PART 0 4.
Other clinical research drugs Molindone hydrochloride (Molindone hydrochloride) is a dopamine D2 receptor (DRD2) antagonist.
On January 18, 1974, the drug was approved by the US FDA for the treatment of schizophrenia. .
Supernus Pharmaceuticals has developed a capsule formulation of moindanone hydrochloride under the license of Afecta Pharmaceuticals for the treatment of behavioral disorders in ADHD patients, and it is currently in clinical phase III
.
In 2014, he was awarded the title of "Fast Track" in the United States for treating impulsive aggressive behavior in ADHD
.
A multi-center, randomized, double-blind, placebo-controlled, phase IIb clinical trial started in November 2011
.
Clinical results showed that low-dose and medium-dose moindanone hydrochloride reached the primary endpoint of the attack remission rate; in the placebo group, dose I group and dose II group, the remission rates of impulsive aggressive behavior were 20% and 52, respectively.
% And 40%
.
A randomized, multi-center, open-label, parallel group, dose range, phase II (NCT00626236) safety and tolerability study in the United States showed that moindanone hydrochloride is safe and well tolerated, with aggressive behavioral problems with key characteristics At the highest dose (40 mg) level it was reduced by 55%
.
Centanafadine hydrochloride is a triple inhibitor of dopamine reuptake, norepinephrine reuptake and serotonin reuptake developed by Euthymics Bioscience Inc (a wholly-owned subsidiary of Otsuka Pharmaceutical), and is currently in the phase III clinical research phase
.
In August 2015, the United States started a double-blind, randomized, placebo-controlled, multicenter, IIb trial (NCT02547428) to evaluate the safety and efficacy of Centanafadine hydrochloride in adult patients with ADHD (n=85)
.
The test results showed that Centanafadine hydrochloride met both the primary and secondary endpoints
.
The results of a single-blind, one-week, placebo-controlled phase II study (NCT01939353) showed that Centanafadine hydrochloride was safe and well tolerated, with significant improvement in ADHD symptoms, and 68% of subjects were considered effective
.
Fasoracetam, a metabolic glutamate receptor agonist developed by Aevi Genomic Medicine, is used to treat ADHD and neuropsychiatric symptoms caused by a related 22q11.
2 deletion syndrome (Digeorge syndrome).
It is currently in clinical phase III research.

.
In August 2017, the United States launched a multi-center, two-part, six-week, double-blind, randomized, placebo-controlled, parallel design, phase II clinical trial (NCT03265119) for children and adolescents with ADHD in the subgroup of mGluR mutation-positive genes
.
The data showed that the trial failed to meet the primary endpoint because the primary endpoint of ADHD-RS reduction in Part A or Part B did not reach statistical significance after 6 weeks of Fasoracetam treatment
.
A II/III study (NCT02777931) evaluated the efficacy and safety of Fasoracetam in adolescents with genetic diseases and ADHD affected by metabolic glutamate receptors
.
The latest results show that of 42 patients with 9 gene mutations (n=18 patients receiving treatment, n=24 patients receiving placebo treatment), 89% of patients receiving treatment (n=16) were in the SAGA trial Clinically and statistically significant responses to Fasoracetam
.
The ADHDRs of the treated patients decreased by 17.
6, and the placebo group decreased by 5.
9
.
In addition, the drug is well tolerated and safe at all doses
.
Edivoxetine Hydrochloride is an adrenergic absorption inhibitor developed by Eli Lilly
.
At present, the highest research and development stage of the drug is clinical phase III, which is used to treat attention deficit disorder with hyperactivity
.
On June 1, 2009, Eli Lilly and Company launched Phase III clinical trials (NCT00922636, NCT00965419) in Canada, Puerto Rico and the United States for the treatment of attention deficit disorder with hyperactivity
.
On August 24, 2021, a Phase III clinical trial (CTR20211990) was carried out in Mainland China by Suzhou Seecro Pharmaceutical Co.
, Ltd.
for the treatment of attention deficit disorder with hyperactivity
.
PART 05.
Conclusion There are currently three methods of treating ADHD: drug therapy, psychotherapy and comprehensive treatment [2]
.
Drug therapy has become an important treatment method for ADHD.
Early, regular, long-term, continuous, all-weather and individualized treatment methods should be followed to achieve good treatment results; improving the remission rate and improving the quality of life of patients are important treatment goals [3]
.
The currently approved therapeutic drugs have relatively large adverse reactions, such as strong addiction, risk of suicidal ideation, serious cardiovascular events, etc.
; and methylphenidate hydrochloride is prohibited from use by children under six years old, these adverse factors greatly limit clinical treatment The use of drugs is not conducive to the treatment of ADHD patients
.
In the future, the development of new mechanisms, low adverse reactions, and differentiated ADHD treatment drugs should be the key research and development goals, which will bring new opportunities to drug research and development companies and institutions, and provide patients with much-needed new drugs
.
For more information about ADHD, please refer to Yaodu Data
.
References: [1] Ditte Demontis, Raymond K.
Walter, Joanna Martin, et al.
Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder[J].
Nature Genetics, 2019, 51: 63–75 [2] Liu Guichun, Liu Shuangquan, Zhao Xiaoying
.
New Psychology Course [M]
.
Beijing: Beijing University of Posts and Telecommunications Press, 2014: 313-316.
[3] Lan Yumei, Yang Chunsong, Zhou Xiaomei
.
Research progress of drugs for the treatment of attention deficit hyperactivity disorder[J]
.
Zhongnan Pharmaceutical, 2017, 15(9): 1269-1271.