Eur Child Adolesc Psychiatry (2006) 15:329–335 DOI 10.1007/s00787-006-0538-3 ORIGINAL CONTRIBUTION

Jana Trebaticka´ Treatment of ADHD with French maritime Sonˇa Kopasova´ Zuzana Hradecˇna´ pine bark extract, Pycnogenol Kamil Cˇinovsky´ Igor Sˇkoda´cˇek Ja´nSˇuba Jana Muchova´ Ingrid Zˇitnˇanova´ Iweta Waczulı´kova´ Peter Rohdewald Zdenˇka Dˇ uracˇkova´

j Abstract Attention Deficit/ examined at start of trial, 1 month Accepted: 27 February 2006 Published online: 13 May 2006 Hyperactivity Disorder (ADHD) is after treatment and 1 month after the most common psychiatric end of treatment period by stan- disorder in children. Pycnogenol, dard questionnaires: CAP (Child an extract from the bark of the Attention Problems) teacher rat- French maritime pine, consisting ing scale, Conner’s Teacher Rating of phenolic acids, catechin, taxif- Scale (CTRS), the Conner’s Parent J. Trebaticka´ (&) Æ S. Kopasova´ olin and procyanidins, has shown Rating Scale (CPRS) and a modi- Z. Hradecˇna´ Æ K. Cˇinovsky´ I. Sˇkoda´cˇek Æ J. Sˇuba improvement of ADHD in case fied Wechsler Intelligence Scale Dept. of Child Psychiatry, reports and in an open study. Aim for children. Results show that 1- Child University Hospital of the present study was to evalu- month Pycnogenol administra- Faculty of Medicine, Comenius University ate the effect of Pycnogenol on tion caused a significant reduction Limbova´ 1 833 40 Bratislava, Slovakia ADHD symptoms. Sixty-one chil- of hyperactivity, improves atten- dren were supplemented with tion and visual–motoric coordi- J. Muchova´ Æ I. Zˇitnˇanova´ Æ Z. Dˇ uracˇkova´ 1 mg/kg/day Pycnogenol or pla- nation and concentration of Institute of Medical Chemistry Biochemistry and Clinical Biochemistry cebo over a period of 4 weeks in a children with ADHD. In the pla- Faculty of Medicine, Comenius University randomised, placebo-controlled, cebo group no positive effects Bratislava, Slovakia doubleblind study. Patients were were found. One month after ter- I. Waczulı´kova´ mination of Pycnogenol admin- Dept. of Nuclear Physics and Biophysics istration a relapse of symptoms Division of Biomedical Physics was noted. Our results point to an Faculty of Mathematics, Physics and Abbreviations: BMI: body mass index; option to use Pycnogenol as a Informatics CAP: Child Attention Problems; CPRS: The Comenius University Conner’s Parent Rating Scale; CTRS: The natural supplement to relieve Bratislava, Slovakia Conner’s Teacher rating Scale; ICD-10: ADHD symptoms of children. International Statistical Classification of P. Rohdewald Diseases and Related Health Problems; j Key words inattention – Institute of Pharmaceutical Chemistry PDW: Prague Wechsler Intelligence Scale University of Mu¨nster hyperactivity – ADHD – for children; WISC: Wechsler Intelligence Mu¨nster, Germany Scale for children Pycnogenol

Introduction achievement and impulsive behaviour [2, 16]. According to a variety of epidemiological data the Attention-deficit/hyperactivity disorder (ADHD) is the incidence of ADHD in children and adolescents ranges most common neuropsychiatric disorder among from 3 to 5 percent. Boys are 2.5 to 9.0 times more likely school-age children [8]. Children with ADHD display to be diagnosed with ADHD compared to girls [1]. 538 ECAP as early onset of symptoms a developmentally inap- According to International Statistical Classification of propriate overactivity, inattention, academic under- Diseases (ICD-10), ADHD is called Hyperkinetic Dis- 330 European Child & Adolescent Psychiatry (2006) Vol. 15, No. 6 ª Steinkopff Verlag 2006 order. In this categorization nosological unit hyperki- nogenol on ADHD symptoms in children in a dou- netic conduct disorder is also included. ble–blind, placebo-controlled study. In the pathophysiology of ADHD the dopaminergic and noradrenergic systems are believed to play an important role. Materials and methods The primary psychopharmacotherapy for ADHD is the prescription of stimulant medication, such as j Patients methylphenidate or amphetamine. These drugs modify uptake of catecholamines (dopamine, nor- • Sixty one out-patients with ADHD, 50 boys and 11 epinephrine) and thus enhance the activity of these girls, treated at the Dept. of Child Psychiatry of the neurotransmitter systems, reducing symptomatology Child University Hospital, average age 9.5 (6– in ADHD [13]. Recently, the nonstimulant highly 14 years) were enrolled in a randomized, double- selective norepinephrine re-uptake inhibitor ato- blind and placebo controlled study. Patients were moxetin has become available for the treatment of randomized to receive either Pycnogenol or pla- ADHD, which effectively reduces symptomatology [3, cebo. 18]. • Selection into the groups (Pycnogenol or placebo) Several reports suggest a beneficial effect of Pyc- was carefully randomized. Teachers, parents and nogenol (Horphag Research Ltd, UK), on patients physicians were not aware of results of randomi- suffering from ADHD. Pycnogenol is a special zation. Randomization was done by the principal standardized extract from the bark of the French investigator responsible for the biochemical, but, maritime pine (Pinus pinaster), corresponding to the not for clinical part. The ratio for Pycnogenol monograph ‘‘Maritime Pine Extract of the US Phar- group to placebo group was 2.5:1. The sample size macopoeia’’ [23]. This extract represents a concen- was estimated assuming the power of 80% (beta of trate of polyphenols, composed of diverse phenolic 20%), the type one error (alpha) of 5% and the acids, catechin, taxifolin and procyanidins with di- number of controls per subject of 0.4. The recom- verse biological and clinical effects [23]. mended number of patients was pre-calculated as Phenolic acids and taxifolin are rapidly absorbed 41 for drug investigation and 16 subjects for pla- and excreted as glucuromides or sulphates, the cebo. We included in the study 44 and 17 patients, procyanidins, biopolymers formed from catechin or respectively. StatDirect 2.3.7 was used for the epicatechin in subunits, are transformed inside the randomization an unpaired random allocation to intestinal tract to active metabolites (valerolactones) intervention or control group and for the sample [9]. size estimation. First case reports about positive effects following • Children were included into study after evaluation supplementation of ADHD children with Pycnogenol of diagnostic criteria of ADHD according to ICD-10 were collected by Passwater [21]. Heimann [11] re- with following diagnoses: Hyperkinetic Disorder ported that Pycnogenol added to treatment with (n=44), Hyperkinetic Conduct Disorder (n=11), dextroamphetamine clearly improved symptoms of Attention Deficit without Hyperactivity (n=6). ADHD of a 10-years-old boy. Withdrawal of Pycnoge- Eighteen patients showed specific learning disabil- nol while continuing dextroamphetamine treatment ities additionally to these symptoms. Patient´s caused a relapse, reinstated Pycnogenol caused again characteristics are given in Table 1. significant improvement. Positive experience with Pycnogenol was also reported by Hanley in her book ‘‘Attention Deficit Disorder’’ [10]. Masao published in Inclusion criteria Japan a success rate of 70% when treating 40 children with 1 mg/kg Pycnogenol [17]. An attempt to dem- Early onset of ADHD—by 6 to 7 years, chronicity—at onstrate reduction of ADHD symptoms in adults failed least 6 months of symptoms, general disposition as in a double-blind, placebo-controlled, comparative restless, inattentive, distractible and disorganized. study with 24 adults [27]. No significant differences Disorders of cognitive function: inattention, dis- were found between placebo, methylphenidate and tractibility, difficulty to persist with any task, diffi- Pycnogenol. As the study could not show a difference culty in selective process to information, disturbance between the active drug, methylphenidate, and placebo, of the executive functions (production, sequention the relevance of these results is questionable. and realization of plans), disturbance of motivation, In our pilot study we found a significant effort and fortitude, visuospacial and memory dis- improvement of ADHD symptoms after Pycnogenol turbance. administration—1 mg/kg/day [28]. Based on these Disorders in control of activity: child’s inability to results, our aim was to determine the effect of Pyc- suppress activity, abnormality in control of activity, J. Trebaticka´ et al. 331 ADHD and Pycnogenol

Table 1 Basic parameters of ADHD patients (M, male; F, female; BMI, Parameters Pycnogenol group Placebo group Body mass index: body mass (kg)/ height2 (m2) Included patients 44 17 Patients finishing the study 41 16 Patients who did not finished the study 3 1 Age (average) 9.5 (6–14) 8,8 (6–12) Body mass (average) (kg) 35.28±10.13 34.80±10.05 BMI 17.41±3.13 16.77±2.61 M/F number, (M/F ratio) 37/7 (5,3:1) 13/4 (3,3:1) Dividing of patients according medication Patients medicated before trial, number 13 (noothropics, neuroleptics) 6 (noothropics, neuroleptics) Patients first time investigated for ADHD 25 8 Patients non-medicated, but 63 under psychiatric observation Dividing of patients according diagnosis Hyperkinetic disorder 34 10 Hyperkinetic conduct disorder 5 6 Attention deficit without hyperactivity 5 1 Comorbid diagnosis Specific learning disabilities 13 5 disorganisation and discontinuation of motoric j Methods activity. Impulsiveness: acting without due reflection, Patients were investigated at the beginning of the trial engaging in rash and sometimes dangerous behav- before study drug administration (start 0), after iours, disturbances of emotions and affectivity. 1 month of treatment (investigation period 1) and 1 month after termination of treatment (wash-out Exclusion criteria period) (investigation period 2). Situational hyperactivity, pervasive developmental In each stage of the study patients were investi- disorders, schizophrenia, other psychotic disorders as gated as follows: mood, anxiety, personality disorder as unsocial 1. Basic psychiatric examination. behaviour, personality change due to a general medical 2. Children were evaluated by teachers and by par- condition, mental retardation, understimulating envi- ents using following scales: ronments, conduct disorder, tics, chorea and other CAP (Child Attention Problems) teacher rating dyskinesias. Patients with acute inflammatory diseases, scale [5] renal and cardiovascular disorders and diabetics were Conner’s Teacher rating Scale (CTRS) [4, 20] excluded from this study, too. Only somatically healthy Conner’s Parent Rating Scale (CPRS) [4, 20] children were included in our study. 3. Psychological investigation according to pedopsy- The study was approved by the Ethical Committee of chiatric standard scheme of psychopathologic the Children University Hospital. Parents gave a written phenomenon received from psychiatric interview consent for participation of their children in the study. with Prague Wechsler Intelligence Scale for chil- dren (PDW), a modified Wechsler Intelligence j Medication Scale for children (WISC) standardized to our population [14]. At breakfast children received 1 mg/kg body weight/ day Pycnogenol during 1 month or placebo with We applied five subtests of Performance Scale. A identical shape and appearance and the same number Weight score was used for each subject. Weight score of tablets/day as in the case of Pycnogenol. Placebo is the sum of values of five subtests of the Perfor- contained lactose (58 mg) and cellulose (65 mg) in mance Scale, standardized for adequate age. Higher tablet. Both tablets, Pycnogenol and placebo were score represents a better psychological state. produced by the same manufacturer, Drug Research Institute, Modra, Slovakia. j Determination of biochemical parameters During 1-month period Pycnogenol, or placebo tablets (equal number of pills as for Pycnogenol) were Blood samples for biochemical analyses were taken administered to patients. Patients were not supple- from venous blood at start, after treatment and after mented with any other drugs including psychotropic wash-out period into commercial tubes with citrate for drugs or with vitamins E and C during the study. determination of individual biochemical parameters. 332 European Child & Adolescent Psychiatry (2006) Vol. 15, No. 6 ª Steinkopff Verlag 2006

Basic biochemical parameters (bilirubin, glucose, the study, three patients from Pycnogenol group and gamma-glutamyl transferase, alkaline phosphatase, one patient from placebo group. Two of them decided aspartate aminotrasferase, alanine aminotransferase, to discontinue their participation in our study after uric acid and lipide profile) were analysed in plasma the first examination, even though they received by standard biochemical procedures using the Hitachi medication. Two patients had to discontinue their 911 automatic analyser (Roche, Switzerland). participation after the second examination, during the wash-out period. Their questionnaires were not re- j Statistical evaluation turned. Data of all patients were evaluated according ‘‘intention-to-treat’’ analysis. The copies of all data obtained from questionnaires All patients were checked for any side effects. No and outputs from computerized analysers were serious side effects were reported. We just observed checked twice before their evaluation and statistical a rise of slowness in one patient and a moderate analysis. gastritic discomfort in another one. Both patients The effect of Pycnogenol or placebo was evalu- belonged to Pycnogenol group and completed the ated with one-way ANOVA for repeated measure- investigation. No side effects were observed in the ments (paired comparisons). For multiple placebo group. comparisons of treatment periods, Wilcoxon’s signed Basic biochemical parameters (bilirubin, glucose, rank test was used. The threshold P value was 0.05/ gamma-glutamyl transferase, alkaline phosphatase, 3=0.016666 (due to Bonferroni correction for triple aspartate aminotrasferase, alanine aminotransferase, comparisons). uric acid and lipide profile) were investigated in For the statistical evaluation of the differences fasting venous blood. All values of biochemical between boys and girls and between Pycnogenol and parameters were in the physiological range before placebo groups as well, Mann–Whitney test was used the trial in both groups. None of analysed bio- as a non-parametric analysis. chemical parameters raised or decreased beyond the For statistical analysis we employed statistical range of physiological values after 1 month of programmes StatsDirect 2.3.7 (StatsDirect Sales, Pycnogenol or placebo administration. Sale, CHeshire M33 3UY, UK) and Statistica 6.0 Based on CAP and CTRS test results, teachers (StatSoft, Inc. 2000). Graphical representation of data evaluated inattention and hyperactivity. Parents rated was made using programmes StatsDirect and Excel hyperactivity and inattention by CPRS tests. Psy- 2000 (Microsoft Co.). chologists evaluated the Weight Score, which sums up five subtests (see chapter ‘‘Methods’’). In the double- blind, placebo-controlled study were evaluated all Results available data of 44 patients treated with Pycnogenol and of 17 patients receiving placebo: The number of investigated patients, age, gender, CAP scores, rated by teachers, revealed no signif- BMI, pre-study medications of patients and number icant differences between groups at start of treatment of patients who failed to complete the study are for hyperactivity as well as for inattention (Fig. 1). indicated in Table 1. Following 1-month of treatment with Pycnogenol, From 61 patients included in the study, 57 patients scores for hyperactivity (P=0.008) as well as for completed the study and four patients dropped out inattention (P=0.00014) dropped significantly com-

Fig. 1 Influence of 1 month A B Pycnogenol administration on *** *** ADHD symptoms evaluated by 10,00 ûûû 10,00 ûû teachers (CAP): – inattention (A) and – hyperactivity (B). empty bar—placebo group; hatched bar—Pycnogenol group. Significance between periods 0 and 1: 5,00 5,00 ***P<0.01. Score Score Significance for Pycnogenol versus placebo in period 1: P<0.01, P<0.05 0,00 0,00 0 1 2 0 1 2 Period of Investigation Period of Investigation J. Trebaticka´ et al. 333 ADHD and Pycnogenol pared to start and also compared to placebo (P=0.044 scores for hyperactivity decreased (Fig. 3), whereas and 0.0067). One month after stop of treatment, in the placebo group no change of hyperactivity or ADHD symptoms were scored at the same level as at inattention was registered. Following 1 month of start of treatment (Fig. 1). treatment with Pycnogenol, the lower score for CTRS scores for inattention, obtained from teach- hyperactivity compared to placebo was marginally ers, differed at start considerably between groups, in significant (P=0.065). contrast to CTRS score for hyperactivity and to CAP The tests for visual–motoric coordination and scores, evaluated by the same teachers. To obtain the concentration—Weight scores—were also different effect of treatment independently from starting val- for placebo and verum group at start. Therefore, ues, CTRS scores at start for each patient were set as changes under medication were evaluated as percen- the 100 percent value and changes during treatment tual changes relative to start. Pycnogenol treatment were calculated as percentage relative to start. With enhanced the Weight scores significantly compared to that CTRS scoring system, teachers noted following start (P=0.019) as well as to placebo (P=0.05), Fig. 4. 1 month of treatment with Pycnogenol a marginally The high values 1 month after stop of treatment for significant reduction (P=0.07) of inattention com- both groups point to a learning effect, giving higher pared to start (Fig. 2) and compared to placebo Weight scores at the 3rd session. (P=0.049). Hyperactivity was also lower compared to start as well as to placebo following Pycnogenol treatment, however, the decrease failed to reach sig- Discussion nificance level (P=0.45 and P=0.28). ADHD symptoms evaluated by parents (CPRS) The results of our double-blind, placebo-controled did not significantly differ at start of treatment study confirm the earlier reports of successful treat- between both groups. Following 1 month of Pyc- ment of ADHD of children with Pycnogenol [17, 21]. nogenol administration, scores for inattention The results reported by Tenenbaum et al. [27], nonsignificantly decreased relative to start, also showing no treatment effect of Pycnogenol in com-

Fig. 2 Influence of 1 month B 140 Pycnogenol administration on A 140 * ADHD symptoms evaluated by teachers (CTRS): ûû 120 – inattention (%) (A) and 120 – hyperactivity (%) (B) Score at period 0=100% empty bar—placebo group; 100 100 hatched bar—Pycnogenol group. Score (%) Significance between periods 0 and 1: Score (%) *0.1>P>0.05. 80 80 Significance for Pycnogenol versus placebo in period 1: P<0.05 60 60 0 1 2 0 1 2 Period of Investigation Period of Investigation

Fig. 3 Influence of 1 month B 15,00 Pycnogenol administration on A 10,00 * ADHD symptoms evaluated û by parents (CPRS): – inattention (A) and – hyperactivity (B) 10,00 hatched bar—Pycnogenol group; empty bar—placebo group. 5,00 Score

Significance between periods 0 and 1: Score *0.1>P>0.05 5,00 Significance for Pycnogenol versus placebo in period 1: 0.1>P>0.05

0,00 0,00 0 1 2 0 1 2 Period of Investigation Period of Investigation 334 European Child & Adolescent Psychiatry (2006) Vol. 15, No. 6 ª Steinkopff Verlag 2006

120 ** and learning dose-dependently, so that they reached ûû nearly the level of the control mice [15]. In a double- blind, placebo-controlled study with elderly intake of Pycnogeol enhanced spatial memory [26]. It remains speculative whether these findings are connected with an increased production of nitric 110 oxide, which works beside its manifold actions also as a neurotransmitter. Pycnogenol stimulates the endothelial nitric oxide synthase in vitro [7] and in vivo [25]. However, whether it also stimulates syn- Score (%) thesis of neuronal nitric oxide synthase, is not known. 100 Nitric oxide (NO) is involved in the regulation of norepinephrine and dopamine release and intake [22]. NO participates in the regulation of normal brain functions, such as memory, learning, modula- tion of wakefulness [29]. NO has also been proposed 90 to act as a neurotransmitter in the long-term poten- 0 1 2 tiation of synapses by traveling backward across the Period of Investigation synapse and enhancing the release of neurotransmit- ter in the presynaptic neuron [24]. In fact, various Fig. 4 Influence of 1 month Pycnogenol administration on visual–motoric reports have indicated that NO may have a role in the coordination and concentration evaluated as Weight score (%) Score at period mechanism of storage and retrieval of information 0=100% empty bar—placebo group; hatched bar—Pycnogenol group. Significance between periods 0 and 1: **P<0.05. Significance for Pycnogenol [19]. The effect of NO on various types of learning has versus placebo in period 1: P<0.05 also been examined with conflicting results [12]. In our study, teachers were able to register the de- parison to placebo, are not contradictory to our crease of hyperactivity and a better attention, for par- findings, because this study could not demonstrate an ents, treatment success for inattention was not that effect of methylphenidate. There was no difference obvious. As reported by Heimann [11], the effect of between the three treatments: methylphenidate, pla- Pycnogenol did not persist for a longer period of time. cebo and Pycnogenol. Whether the failure to detect Control after 1 month wash-out period demonstrated a the effect of the established drug, methylphenidate, relapse of symptoms, demonstrating that Pycnogenol was caused by the fact that adults had been treated or has an effect on ADHD symptoms but seems not to by methodological factors, cannot be judged. How- change the underlying fundamental processes. ever, the lack of a difference between an active drug During our experiments we noted that treatment and placebo found by Tenenbaum et al. suggests that was not significantly effective for girls, in contrast to the study also had not the power to detect a possible boys. Because only six girls were in the Pycnogenol difference between placebo and Pycnogenol treat- group, we cannot judge whether we observed a true ment success. gender-specific effect. Investigation with greater Our findings seem to present an alternative to numbers of girls is needed to see whether there is a treatment with existing drugs for parents fearing the gender-specific effect of Pycnogenol . The relative adverse effects of established drugs, however, results small number of 44 patients treated with Pycnogenol of our study have to be further confirmed by studies and the short duration of the study limits the gener- involving a greater number of patients. alization of our findings. However, the small, but The mechanism of the treatment success remains significant success of treatment together with the to be elucidated. Analysis of urine of the patients in small incidence of mild side effects suggest that Pyc- our study revealed a lower excretion of catecholam- nogenol could find a place as an alternative treat- ines compared to placebo [6], pointing to an influence ment of ADHD of children. of Pycnogenol on catecholamine formation or on metabolism. Another hint that Pycnogenol influences cogni- j Acknowledgements This study was supported by Horphag Res. tive functions can be deduced from experiments with Ltd. grant, partly by VEGA Grants No. 1/1157/04, 1/3037/06, Grant VV MVTS 03/LF of Ministry of Education of SR, by Drug Research senescence-accelerated strains of mice. These mice Institute, Modra, SR and Mind&Health, civil association. Authors loose memory and learning capabilities early in wish to thank to Assoc. Prof. P. Blazˇ´ıcˇek, PhD for the biochemical comparison to normal mice. Feeding the senescence- analyses, to Mrs. Lˇ’. Chandogova´ and L. M´ıkova´ for their technical accelerated mice with Pycnogenol restored memory assistance. J. Trebaticka´ et al. 335 ADHD and Pycnogenol

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