The efficacy of non-psychostimulant therapy in the Attention Deficit Hyperactivity Disorder

SUMMARY

Attention Defi cit Hyperactivity Disorder (ADHD) is a major public health problem due to its high prevalence. In the present it is considered the most commonly neuropsychiatric disorder encountered in the child and adolescent. Th e medication needed to treat ADHD is part of the multimodal approach that includes education, counseling, behavioral treatment, and family responsibility for the correct administration of the medication. Th e aim of this study is to track the clinical development of patients with ADHD based on the non-psychostimulant treatment administered. Th e main objective of the study was to quantify the effi cacy of the drug therapy in alleviation of ADHD symptoms comparing the total average scores obtained on the following scales : ADHD Rating Scale -IV, CGAS – Children’s Global Assessment Scale, CGI-S – Clinical Global Impression Scale – Severity and CGI-I – Clinical Global Impression Scale – Improvement at 6 months, 1 year and 2 years from the start of treatment.

Key words: ADHD, non-psychostimulant treatment, Atomoxetine

INTRODUCTION

Attention Deficit Hyperkinetic Disorder (ADHD) is a neurobiological behavioural disorder of the child, adolescent and adult characterized by problems of concentration, hyperactivity and impulsivity caused by an imbalance of chemical neurotransmitters in the brain (dopamine and noradrenaline) affecting those parts of the brain responsible for self-monitoring and for suppressing inappropriate behaviours[1].

At present, ADHD is a major public health problem due to its high prevalence. Currently, it is considered the most common neuropsychiatric disorder in the child and adolescent. The cause of the attention deficit hyperactivity disorder is not fully known yet. Genetic, environmental (natal and perinatal), familial and psychosocial factors have been incriminated [2].

There are theories that accuse the effect of dopamine and noradrenaline neurotransmitters in the onset of ADHD. The response of patients with ADHD to non-psycho-stimulants medication which facilitate dopamine release that are used to treat this pathology has led to speculation that, in some areas of the brain, these neurotransmitters have deficiencies in the transmission of nerve impulses. In children diagnosed with ADHD, imaging investigations revealed a decrease in cerebral activity in the frontal and parietal cortex (with a role in perception and localization), in the basal lymph nodes and in cerebellum. Also, morphofunctional changes have been detected at the level of the hippocampus with a role in the phenomena of association and recognition, at the limbic system with a role in the control of behaviour and emotions, at the prefrontal cortex responsible for the analysis processes and at the reticulate activator system with a role in activation and alert [3].

The diagnosis of ADHD is based on the DSMIV or ICD-10 criteria. For a correct diagnosis it is necessary to carry out a rigorous assessment of the child by a multidisciplinary team consisting of a psychiatrist, a paediatrician and a psychologist [4].

The approach to the attention deficit hyperkinetic disorder is multimodal, involving both drug therapies and psychotherapy. Nowadays, the first-line drugs used to treat ADHD are divided into two major classes: psychostimulant and non-psycho-stimulant medications [5].

Non-psycho-stimulant medications make a blockage in the neuronal synapse, resulting in a relative increase of noradrenaline at this level. The benefits of non-psycho-stimulant medications consist in a long duration of action, ease of administration, requiring a single dose per day, the absence of rebound phenomena and of insomnia, low risk of abuse, and flexibility in dose adjustment. Atomoxetine is the only representative of this class approved in our country in children and adolescents [6].

Psycho-stimulants correct dopamine deficits in the central nervous system by blocking dopamine uptake mechanisms at this level in increasing the extracellular level of dopamine. There are studies that have shown that psycho-stimulants gradually regulate the functioning of neurons in the prefrontal cortex. The most commonly used drugs in this class are methylphenidate and amphetamines [6].

Evaluation of the efficacy of drug therapy in Attention Deficit Hyperactivity Disorder is achieved through ADHD-specific scales and other behavioural scales. In particular, the scores obtained by patients on these scales at baseline are compared with those obtained after drug therapy is instituted.

PURPOSE AND OBJECTIVES

The purpose of this paper is to track the clinical evolution of patients with ADHD based on nonpsycho-stimulant treatment (with atomoxetine). The main objective of the study was to quantify the efficacy of drug therapy in amending ADHD symptoms by comparing the total mean scores obtained on the following scales: ADHD Rating Scale-IV, CGAS, CGI-S and CGI-I at 6 months, 1 year and 2 years respectively after the treatment was instituted.

MATERIAL AND METHOD

The study was conducted in a total of 60 patients diagnosed with ADHD, the combined subtype, aged between 7 and 18 years, admitted to the Department of Paediatric Psychiatry at the Emergency Clinical Hospital “Louis Ţurcanu” Timişoara between 2011 and 2016. The parents or legal guardians of the children selected to participate in the study gave their written consent for participation being informed on all aspects related to the study.

Patients were diagnosed with the combined subtype of ADHD according to DSM-IV-TR and ICD-10 criteria. The medical treatment was prescribed by the attending physician at the Paediatric Psychiatry Section. Retrospectively, patient evolution was analysed over a two-year period, depending on the non-psychostimulant medication administered.

Inclusion criteria

– the subjects included in the study were aged 7-18;

– they had at least one admission to the Psychiatric Section of the Timisoara Emergency Clinical Hospital and remained on the clinic record for at least two years;

– patients met DSM IV-TR and ICD 10 criteria for the diagnosis of ADHD;

– they received treatment with non-psychostimulant drugs;

– consent of legal parents / carers of the subjects was given after receiving information on the purpose of the study and on what it was supposed to be done;

Exclusion criteria

– patients with predominantly inattentive subtype and predominantly hyperactive / impulsive subtype were excluded;

– patients with associated co-morbidities and those with moderate and severe mental retardation were excluded, too;

– patients under the age of 7 years or those older than 18 years were not included in the study.

WORKING TOOLS

All patients enrolled in the study were assessed using the following scales: ADHD Rating Scale-IV, Children’s Global Assessment Scale (CGAS) and Clinical Global Impression Scale (CGI)- the clinical severity and the clinical improvement components.

The ADHD Rating Scale-IV is a scale that includes 18 items, each item received between 0 and 4 points. The maximum score that can be obtained is 54. The higher the score, the more severe the disorder is. To assess the efficacy of the drug therapy with the ADHD Rating Scale-IV, baseline score was compared with the score at 6 months, one year and two years after the start of the treatment.

Also, to assess the clinical severity of the symptomatology, the CGI scale – the severity assessment component – was used. A score of 1 to 7 was given (1 if the subject had no symptoms, 7 if the subject had extremely severe symptoms).

Clinical improvement of symptomatology was assessed using the CGI-scale, the component of clinical improvement assessment. For this, a score of 1 to 7 was given (1 if the symptoms improved a group/ cohort, 7 if the patient’s condition got worse).

The assessment of the evolution of the overall functioning of children was done using the Children’s Global Assessment Scale (CGAS). The score on this scale may vary between 10% and 100%. A percentage of 10 represents the maximum psychiatric alteration, and starting with a 70 percent, it can be said that the overall functionality of the assessed child is within normal parameters.

Statistical analysis

Statistical data processing was done using Excel 2007 (version 14.0). Depending on the variables processed to evaluate statistical significance we used unpaired student t tests and t student tests for dependent samples. The condition that they be statistically significant is that the result should be p <0.05.

RESULTS:

1.Assessment of the efficacy of the non-psychostimulant treatment following the evolution over time of the scores obtained on the ADHD-RS-IV There was a significant reduction in total mean scores on the ADHD-RS-IV from baseline to 6 months, one year and two years after the start of treatment (p <0 value 0,05). The total mean scores on the ADHD-RS-IV scale are shown in Table I and fig. 1

2.Assessment of the efficacy of the non-psychostimulant treatment following the evolution over time of the scores obtained on the CGI-S Scale (symptom severity component): We noted that there was a significant reduction in 6-month scores (p = 0.049), respectively one year after treatment (p = 0.033), followed by a plateau phase in which the total mean scores remain unchanged. Thus, the total scores range from 5 (marked effect) to 4 (moderate effect) after 6 months, respectively 3 (slight effect) after 1 year. At 2 years the average of total scores remains unchanged (table II, fig. 2).

3.Evaluation of the efficacy of the non-psychostimulant treatment following the evolution over time of the scores obtained on the Clinical Global Impression Scale – Improvement Scale (CGI-I): The CGI Improvement Assessment Component includes 7 items listed from 1 to 7, which show the improvement in ADHD symptoms (1 if the symptoms have improved greatly, 7 if the patient’s condition has greatly worsened). Therefore, on this scale, the lesser the scores are, the improvement of the disorder is better. On these scale the mean of scores obtained at 6 months after the start of treatment was 2 (patient’s condition improved significantly), at 1 year the mean of the ratings remained still 2, and at 2 years the mean was 1 (patient’s condition improved very much) (table III, fig. 3).

4.Assessment of the efficacy of non-psychostimulant therapy following the evolution over time of the scores obtained on the Children’s Global Assessment Scale (CGAS): The test started at an operating level of 38%. After the beginning of the intervention, significant increase in functional level was observed at 6 months (p <0.01), reaching an average of 65%. Also, 1 year after the treatment administration, there was a significant increase in the level of functioning, reaching an average of 73% (p = 0.011). At two years, the level of operation reached 80% (table IV, fig. 4).

DISCUSSION

The Attention Deficit Hyperkinetic Disorder (ADHD) is the most common neuropsychiatric disorder in the child and adolescent. Symptoms that predominate in this disorder are inattention, hyperactivity and impulsivity. These symptoms adversely affect the child’s performance as well as her/ his  interpersonal relationships. In the absence of adequate childhood treatment, ADHD has an unfavourable prognosis and may   result in adolescence complications that could persist during maturity, too (behavioural disorders, psychoactive substance use, personality disorder, etc.). It is very important for the treatment to be  administered as soon as possible after a correct diagnosis is established, which also addresses the associated co-morbidities. Nowadays, the medical treatment of ADHD is represented by psycho-stimulant and non-psycho-stimulant drugs.

The purpose of this paper was to evaluate the clinical progress of patients with attention deficit in relation to non-psycho-stimulant treatment administered. For this, we compared the total mean scores obtained by patients treated with atomoxetine on the following scales: ADHD Rating Scale-IV, Children’s Global Assessment Scale (CGAS) and Clinical Global Impression Scale – the Components of  Clinical Severity Assessment and Clinical Improvement Assessment (CGI-S and CGI-I).

Using the total mean scores obtained on the ADHD-RS – IV, we quantified the efficacy of the drug treatment in reducing the symptoms of ADHD under treatment. Significant alleviation of symptoms was found at 6 months, 1 year and 2 years, respectively, from the start of treatment.

The clinical severity rating component of the Clinical Global Impression Scale has been instrumental in assessing the efficacy of drug therapy in alleviating the severity of symptoms after treatment. We noted that there was a significant reduction in the 6-month scores, respectively one year after treatment, followed by a plateau phase, in which the total mean scores remain unchanged. Thus, the mean of total scores ranges from 5 (markedly ill) to 4 (moderately ill) after 6 months and 3 (mildly ill) after 1 year. At 2 years, the total score mean remains unchanged.

The Clinical Improvement Assessment component of the CGI scale evaluates the degree of post-treatment improvement of the patient’s condition. Scores that can be awarded on this scale range between 1 and 7 (the lesser the score is, the better the patient’s condition). At

6 months after the start of the treatment, the mean of scores was 2 (this score is given if the patient’s condition improved greatly), at one year there was no change, the mean of the scores being also 2, and two years later, again, an improvement was noted, with the average score reaching 1 (i.e. the patient’s condition is greatly improved).

The last scale I used to evaluate the efficacy of non-psycho-stimulant therapy was the CGAS that assesses the overall functioning of ADHD children and adolescents. The test started at an operating level of 38%. After administration of treatment, an extremely significant increase in functional level was observed at 6 months (p <0.01), reaching a mean of 65%. Also, 1 year after the treatment administration, there was a significant increase in the level of functioning, reaching an average of 73% (p = 0.011). At two years, the level of functioning reached 80%.

Most studies conducted so far suggest that nonpsycho-stimulants are effective in treating ADHD.

In 2003, Michelson et al. performed eight control studies and six open-label studies in 2938 subjects to assess the efficacy of atomoxetine in ADHD patients.

An initial 10-week study on 536 subjects revealed a 30% reduction in total mean scores on Conners Scale  after atomoxetine administration, compared to 20% representing the drop of total mean scores when a placebo drug was administered. Similar results have been obtained in the case of reduction the symptoms of inattention and hyperactivity / impulsivity [7].

At the same time, in an open-label study in 2006, Kratochvil et al. suggest that atomoxetine is as effective as methylphenidate in treating ADHD, both drugs having very good effects in alleviating attention deficit and hyperactivity / impulsivity [8].

CONCLUSIONS

1. Non-psycho-stimulating therapy significantly improve the symptoms of attention deficit hyperkinetic disorder. There is a significant reduction in the frequency with which the symptoms occur in all three post-treatment assessments.
2. There was a significant reduction in the severity of ADHD symptoms at six months and at one year from the start of treatment.
3. Non-psycho-stimulating therapy significantly improve the overall functioning of children and adolescents with ADHD.

REFERENCES

1. Conners CK. Attention-defi cit/hyperactivity disorder: historical development and overview. J Atten Disord. 2000;3:173–191. doi: 10.1177/108705470000300401.
2. Biederman, J., Faraone, S. V., Keenan, K., Knee, E., et al. (1990). Family-genetic and psychosocial risk factors in DSM-III attention defi cit disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 526-533.
3. Malenka RC, Nestler EJ, Hyman SE (2009). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp.  266, 315, 318– 323. ISBN 978-0-07-148127-4. Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.
4. Dulcan, Mina K.; Lake, MaryBeth (2011). “Axis I Disorders Usually First Diagnosed in Infancy, Childhood or Adolescence: Attention-Defi cit and Disruptive Behavior Disorders”. Concise Guide to Child and Adolescent Psychiatry (4th illustrated ed.). American Psychiatric Publishing. p. 34. ISBN 978-1-58562-416-4.
5. Gentile JP, Atiq R, Gillig PM (August 2006). “Adult ADHD: Diagnosis, Diff erential Diagnosis, and Medication Management”. Psychiatry (Edgmont).  pp: 2530. PMC 2957278 . PMID  20963192
6. Prince JB – Pharmacotherapy of attention-defi cit hyperactivitydisorder in children and adolescents: update on new stimulantpreparations, atomoxetin and novel treatments. Child Adolesc Psychiatr Clin N Am, 2006, 15, pp 13-50.
7. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53:112–120.
8. Kratochvil CJ, Wilens TE, Greenhill LL, et al. Eff ects of longterm atomoxetine treatment for young children with attention-defi cit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006;45:1–