Özgür Albayrak

Substitution of (R,S)-Methadone by (R)-Methadone: Impact on QTc Interval

BACKGROUND Methadone is administered as a chiral mixture of (R,S)-methadone. The opioid effect is mainly mediated by (R)-methadone, whereas (S)-methadone blocks the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias. METHODS To investigate whether substitution of (R,S)-methadone by (R)-methadone could reduce the corrected QT (QTc) interval, (R,S)-methadone was replaced by (R)-methadone (half-dose) in 39 opioid-dependent patients receiving maintenance treatment for 14 days. (R)-methadone was then replaced by the initial dose of (R,S)-methadone for 14 days (n = 29). Trough (R)-methadone and (S)-methadone plasma levels and electrocardiogram measurements were taken. RESULTS The Fridericia-corrected QT (QTcF) interval decreased when (R,S)-methadone was replaced by a half-dose of (R)-methadone; the median (interquartile range [IQR]) values were 423 (398-440) milliseconds (ms) and 412 (395-431) ms (P = .06) at days 0 and 14, respectively. Using a univariate mixed-effect linear model, the QTcF value decreased by a mean of -3.9 ms (95% confidence interval [CI], -7.7 to -0.2) per week (P = .04). The QTcF value increased when (R)-methadone was replaced by the initial dose of (R,S)-methadone for 14 days; median (IQR) values were 424 (398-436) ms and 424 (412-443) ms (P = .01) at days 14 and 28, respectively. The univariate model showed that the QTcF value increased by a mean of 4.7 ms (95% CI, 1.3-8.1) per week (P = .006). CONCLUSIONS Substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value. A safer cardiac profile of (R)-methadone is in agreement with previous in vitro and pharmacogenetic studies. If the present results are confirmed by larger studies, (R)-methadone should be prescribed instead of (R,S)-methadone to reduce the risk of cardiac toxic effects and sudden death.

Genetic aspects in attention-deficit/hyperactivity disorder

SummaryAttention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder among children and adolescents with high heritability. Molecular genetic findings support the thesis that dopaminergic, serotonergic, and noradrenergic neurotransmission pathways account for the etiology of this complex disease. Genetic research comprises formal genetic studies, candidate gene studies, linkage analyses, and recently large-scale genome wide association studies, gene-environement interaction studies, and pharmacogenetics. This article comprehensively reviews the latest findings on the genetics of ADHD.

Genome-wide association study in German patients with attention deficit/hyperactivity disorder

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome‐wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM‐IV criteria; Human660W‐Quadv1; Illumina, San Diego, CA) and on 1,300 population‐based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P‐values (best P‐value: 8.38 × 10−7) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P‐values (P‐values ≤ 7.57 × 10−5) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect‐size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta‐analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect‐size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome‐wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P‐values compared to SNPs within random sets of genes of the same size. We did not find genome‐wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

Treating childhood obesity: Family background variables and the child's success in a weight‐control intervention

OBJECTIVE To analyze whether caregiver and family characteristics predict success in a family-based lifestyle intervention program for children and adolescents. METHOD Participants were 111 overweight and obese children (7-15 years) who attended a family-based weight-reduction program. Body mass index (BMI) and BMI standard deviation scores (BMI-SDS) of index child, and BMI of family members, family adversity characteristics, depression, and attachment attitudes of the primary caregiver were assessed. RESULTS Risk of nonresponse (<or=5% reduction of BMI-SDS or dropout) was elevated in older children, cases with obese sibling(s), maternal depression, and avoidant attachment attitude. In a logistic regression analysis, maternal depression, attachment attitude, and age of index child explained common variance whereas the presence of obese siblings explained unique variance in nonresponding. DISCUSSION To meet the specific needs of all participating families and to prevent the discouraging experience of failure in weight-control interventions, our data suggest that special support should be provided to adolescents with obese siblings, and cases of maternal depression, and avoidant attachment attitude.

Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder†

Children with attention‐deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome‐wide association study (GWAS) for ADHD based on 495 patients and 1,300 population‐based controls and performed in silico analyses of the SNPs in an ADHD meta‐analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X‐type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10−4; Pcorr = 0.01). In the meta‐analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein‐coupled receptor, family C, group 5, member B; P = 7.2 × 10−4; Pcorr = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine‐6‐phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen‐activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta‐analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.

Does food addiction exist? A phenomenological discussion based on the psychiatric classification of substance-related disorders and addiction.

The relationship between overeating, substance abuse and (behavioral) addiction is controversial. Medically established forms of addiction so far pertain to substance use disorders only. But the preliminary Diagnostic and Statistical Manual for Mental Disorders V (DSM V) suggests replacing the previous category ‘Substance-Related Disorders’ with ‘Addiction and Related Disorders’, thus for the first time allowing the diagnosis of behavioral addictions. In the past psychiatrists and psychologists have been reluctant to systematically delineate and classify the term behavioral addiction. However, there is a broad overlap between chemical and behavioral addiction including phenomenological, therapeutic, genetic, and neurobiological aspects. It is of interest to point out that the hormone leptin in itself has a pronounced effect on the reward system, thus suggesting an indirect link between overeating and ‘chemical’ addiction. Thus, leptin-deficient individuals could be classified as fulfilling criteria for food addiction. In our overview we first review psychological findings in chemical (substance-based) and subsequently in behavioral addiction to analyze the overlap. We discuss the diagnostic validity of food addiction, which in theory can be chemically and/or behaviorally based.

Conditions of Long-term Success in a Lifestyle Intervention for Overweight and Obese Youths

OBJECTIVE: Childhood lifestyle interventions usually involve the families. However, knowledge of family characteristics that promote or constrain a childs weight-reduction outcome is limited. Candidates for such factors might be family characteristics that have proven to be associated with social adjustment (development) in childhood. Thus, we analyzed whether family adversity, maternal depression, and attachment insecurity predict long-term success in childrens weight reduction. PATIENTS AND METHODS: Participants in the study were 111 parent-child dyads with overweight and obese children/adolescents (BMI mean: 29.07 [SD: 4.7] [range: 21.4–44.9]; BMI SD score mean: 2.43 [SD: 0.44] [range: 1.31–3.54]) aged between 7 and 15 years. The families took part in a best-practice lifestyle intervention of 1 years duration. A longitudinal analysis with 3 assessment waves (baseline, conclusion, 1-year follow-up) was conducted. RESULTS: Hierarchical regression analyses revealed that long-term success (at least 5% weight reduction by the 1-year follow-up) versus failure (dropping out or less weight reduction) was significantly predicted by the set of psychosocial variables (family adversity, maternal depression, and attachment insecurity) when we controlled for familial obesity, preintervention overweight, age, and gender of the index child and parental educational level. Maternal depression proved to be the best predictor. Maintenance of weight reduction between the conclusion of the program and the 1-year-follow-up was also predicted by the set of psychosocial variables. Maternal insecure-anxious attachment attitudes best predicted this criterion. CONCLUSIONS: Although cross-validation is required, our results are the first evidence for proximal and distal family characteristics linked to long-term weight-reduction outcomes. The results suggest a need to create tailored intervention modules that address the difficulties of these families.

Links between psychopathological symptoms and disordered eating behaviors in overweight/obese youths

OBJECTIVE Among overweight and obese youths, rates of depression, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) are elevated. We analyze whether these emotional and behavioral problems are associated with specifically disordered eating pattern. METHOD Participants in the study were 128 overweight and obese children/adolescents (BMI: m = 29.3, s = 4.5; BMI-SDS: m = 2.5, s = 0.4) between 8 and 15 years. Structured psychiatric assessments were conducted adopting a multimethod, multiinformant approach. RESULTS Children/adolescents with ODD symptoms showed increased eating in response to external cues and binge eating. ADHD symptoms were not associated with disordered eating behaviors. Children/adolescents with symptoms of depression and anxiety showed emotional and binge eating. In particular, overweight girls with symptoms of depression showed restrained eating. DISCUSSION Our results point to specific eating problems in overweight/obese children with ODD and depression/anxiety symptoms. The findings could help to tailor interventions to optimally meet the specific needs of overweight children with emotional and behavioral problems.

Leptin treatment of patients with anorexia nervosa? The urgent need for initiation of clinical studies.

The core symptomatology of anorexia nervosa can be conceptualized as the intertwining of the primary behaviors with the psychological and physical consequences of starvation [1, 2]. The onset of this eating disorder is seemingly unspectacular: similar to many other females of the respective age group most patients strive to lose weight by dieting, some additionally increase their physical activity; a not well specified percentage of patients starts off with weight loss unrelated to the desire to lose weight, such as a depressed mood or obsessive–compulsive behaviors related to food and its intake. While AN patients as a group have elevated rates of premorbid psychopathology, an individual patient may present without a history of mental problems. Indeed, patients are frequently characterized as well (or even overly) adjusted prior to initial weight loss. After weight loss sets in, patients are rewarded internally by for instance a positive experience of control over their eating behavior and their body weight and potentially externally by positive remarks of peers and family members. At the same time the physiological response to a reduced energy intake sets in, which in its continuation entails the well-known symptoms of starvation encountered in acutely ill patients. This intertwining of the primary behaviors leading to initial and prolonged weight loss and the ongoing adaptation to starvation in total result in the characteristic clinical phenotype upon presentation of a patient, which includes somatic, cognitive and behavioral symptoms. A patient at this stage will potentially state that the initial desire to lose weight was replaced by an urge or compulsion to continue to do so ultimately leading to a sense of loss of control over energy intake and body weight. The therapeutic armamentarium available for AN patients must be considered as meager. Weight reconstitution is considered as paramount; inpatient treatment by an experienced team is required if underweight and starvation symptoms have resulted in a critical condition (http:// www.nice.org.uk/nicemedia/live/10932/29220/29220.pdf). Both psychotherapeutic and psychopharmacological trials have been hampered by the high drop-out rates characteristic of AN patients. A recent study that compared specialist supportive clinical management, cognitive behavior therapy and interpersonal psychotherapy revealed no significant differences on any pre-selected primary, secondary or tertiary outcome measures among the three psychotherapies after a mean follow-up of 6.7 years [3]; specialist supportive clinical management led to a more rapid response than interpersonal psychotherapy. Antidepressants and in particular selective serotonin reuptake inhibitors have not proven beneficial for treating the disorder itself or the frequent comorbid depression. There is evidence that olanzapine is helpful during the acute phase of AN [4]. The treatment costs for AN are high; in Germany it was estimated that the total direct treatment costs amounted to 195 million euros in 1999 which implied mean annual costs per patient of approximately 5,300 euros [5]. In light of these meager and costly therapeutic options it is our obligation to be on the lookout for novel treatments. We and others have proposed treating acutely ill AN patients with leptin for more than a decade; nevertheless, J. Hebebrand (&) Ö. Albayrak Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany e-mail: Johannes.Hebebrand@uni-due.de

Successful methylphenidate treatment of early onset extreme obesity in a child with a melanocortin-4 receptor gene mutation and attention deficit/hyperactivity disorder

We present the case report of a 2 year old boy with early onset extreme obesity (body mass index (BMI) 34.2 kg/m²; body mass index standard deviation score (BMI-SDS) 5.4) who is heterozygous for a non-conservative functionally relevant melanocortin MC(4)receptor mutation (Glu308Lys) and who also showed severe symptoms of attention deficit/hyperactivity disorder (ADHD). Treatment with the stimulant methylphenidate led to a sharp decrease of BMI to 21.8 kg/m² (BMI-SDS 2.8) within 24 months. We discuss potential mechanisms for this unusually large weight loss and suggest a potential link between the melanocortinergic and the dopaminergic systems, and the sympathetic nervous system. The potential benefit of methylphenidate in obese melanocortin MC(4)receptor mutation carriers with and without co-morbid ADHD warrants further studies.