Mona Abdel-Hamid

Effects of Group Psychotherapy, Individual Counseling, Methylphenidate, and Placebo in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial

IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high prevalence in adulthood. There is a recognized need to assess the efficacy of psychotherapy in adult ADHD. OBJECTIVE To evaluate the efficacy of cognitive behavioral group psychotherapy (GPT) compared with individual clinical management (CM) and that of methylphenidate hydrochloride compared with placebo. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter, randomized clinical trial of 18- to 58-year-old outpatients with ADHD from 7 German study centers. Patients were recruited between January 2007 and August 2010, treatment was finalized in August 2011, and final follow-up assessments occurred in March 2013. INTERVENTIONS Sessions of GPT and CM were held weekly for the first 12 weeks and monthly thereafter (9 months). Patients received either methylphenidate or placebo for 1 year. MAIN OUTCOMES AND MEASURES The primary outcome was the change in the ADHD Index of the Conners Adult ADHD Rating Scale from baseline to the end of the 3-month intensive treatment (blinded observer ratings). Secondary outcomes included ADHD ratings after 1 year, blinded observer ratings using the Clinical Global Impression Scale, and self-ratings of depression. RESULTS Among 1480 prescreened patients, 518 were assessed for eligibility, 433 were centrally randomized, and 419 were analyzed as randomized. After 3 months, the ADHD Index all-group baseline mean of 20.6 improved to adjusted means of 17.6 for GPT and 16.5 for CM, with no significant difference between groups. Methylphenidate (adjusted mean, 16.2) was superior to placebo (adjusted mean, 17.9) (difference, -1.7; 97.5% CI, -3.0 to -0.4; P = .003). After 1 year, treatment effects remained essentially stable. Descriptive analyses showed that methylphenidate was superior to placebo in patients assigned to GPT (difference, -1.7; 95% CI, -3.2 to -0.1; P = .04) or CM (difference, -1.7; 95% CI, -3.3 to -0.2; P = .03). Regarding depression, no significant differences were found. In contrast, GPT was superior to CM for all visits in the Clinical Global Impression global assessment of effectiveness. CONCLUSION AND RELEVANCE Highly structured group intervention did not outperform individual CM with regard to the primary outcome. Psychological interventions resulted in better outcomes during a 1-year period when combined with methylphenidate as compared with placebo. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN54096201.

The impact of acute tryptophan depletion on attentional performance in adult patients with ADHD.

To date, the impact of the neurotransmitter serotonin (5‐HT) on different neuropsychological functions in adults with attention deficit hyperactivity disorder (ADHD) is underinvestigated. We aimed to examine the effects of acute tryptophan depletion (ATD) and the resulting reduction in central nervous 5‐HT synthesis on target/non‐target discrimination ability and sustained attention in adults with ADHD using an AX‐Continuous Performance Test (AX‐CPT).

The Effects of Acute Tryptophan Depletion on Reactive Aggression in Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) and Healthy Controls

Background The neurotransmitter serotonin (5-HT) has been linked to the underlying neurobiology of aggressive behavior, particularly with evidence from studies in animals and humans. However, the underlying neurobiology of aggression remains unclear in the context of attention-deficit/hyperactivity disorder (ADHD), a disorder known to be associated with aggression and impulsivity. We investigated the effects of acute tryptophan depletion (ATD), and the resulting diminished central nervous serotonergic neurotransmission, on reactive aggression in healthy controls and adults with ADHD. Methodology/Principal Findings Twenty male patients with ADHD and twenty healthy male controls were subjected to ATD with an amino acid (AA) beverage that lacked tryptophan (TRP, the physiological precursor of 5-HT) and a TRP-balanced AA beverage (BAL) in a double-blind, within-subject crossover-study over two study days. We assessed reactive aggression 3.25 hours after ATD/BAL intake using a point-subtraction aggression game (PSAG) in which participants played for points against a fictitious opponent. Point subtraction was taken as a measure for reactive aggression. Lowered rates of reactive aggression were found in the ADHD group under ATD after low provocation (LP), with controls showing the opposite effect. In patients with ADHD, trait-impulsivity was negatively correlated with the ATD effect on reactive aggression after LP. Statistical power was limited due to large standard deviations observed in the data on point subtraction, which may limit the use of this particular paradigm in adults with ADHD. Conclusions/Significance Together with previous findings, the data provide preliminary evidence of an inverse association between trait-impulsivity and the ATD effect on reactive aggression after LP (as assessed by the PSAG) in patients with ADHD and that this relationship can be found in both adolescents and adults. Because of limited statistical power larger sample sizes are needed to find main effects of ATD/BAL administration on reactive aggression in adults with ADHD.

German Validation of the Conners Adult ADHD Rating Scale–Self-Report: Confirmation of Factor Structure in a Large Sample of Participants with ADHD

Objective: The Conners Adult ADHD Rating Scales (CAARS) assess symptoms specific to adults that are frequently used and have been translated into German. The current study tests the factor structure of the CAARS in a large sample of German adults with ADHD and compares the means of the CAARS subscales with those of healthy German controls. Method: CAARS were completed by 466 participants with ADHD and 851 healthy control participants. Confirmatory factor analysis was used to establish model fit with the American original. Comparisons between participants with ADHD and healthy controls and influences of gender, age, and degree of education were analyzed. Results: Confirmatory factor analysis showed a very good fit with the model for the American original. Differences between ADHD participants and healthy controls on all Conners Adult ADHD Rating Scales–Self-Report (CAARS-S) subscales were substantial and significant. Conclusion: The factor structure of the original American model was successfully replicated in this sample of adult German ADHD participants.

No clear effects of acute tryptophan depletion on processing affective prosody in male adults with ADHD

Adults with attention deficit hyperactivity disorder (ADHD) have difficulties processing affective prosody, and research evidence demonstrates the importance of brain serotonin (5‐HT) in the neurobiology of ADHD. This study aimed to investigate whether diminished brain 5‐HT synthesis, as achieved by acute tryptophan depletion (ATD), can impair the processing of affective prosody in adults with ADHD.

Acute tryptophan depletion – converging evidence for decreasing central nervous serotonin synthesis in rodents and humans

We read the comment provided by Simon N. Young (1) on the articles (2–5) in the special issue of Acta Psychiatrica Scandinavica (6) dealing with the acute tryptophan depletion (ATD) methodology with great interest. ATD is a pharmacological method designed to lower central nervous system (CNS) synthesis of the neurotransmitter serotonin (5-HT) for a brief period that can also be used in both adults and young people (7). As 5-HT plays an important role in behavioral inhibition (8– 10) and other important processes in the brain (11–14), ATD is a translational method to study the effects of changes in CNS 5-HT function that has particular value, as discussed at a recent symposium dedicated to the role of 5-HT in psychopathology (7–11, 15). The author of this particular comment expressed concerns that ATD might not always decrease CNS 5-HT synthesis and that the lack of the amino acid histidine (HIS) in the depletion mixtures used might influence the results due to the potential role of 5-HT–histamine interactions in any observed outcome. We appreciate the comments made and would like to address the issues raised, point by point. Young argues that ‘there is no evidence that ATD does always decrease serotonin release (in humans)’. This is contradictory by decades of work in rodents and in humans demonstrating that ATD can decrease 5-HT synthesis and release in rodents and lower 5-HIAA in human CSF (16–19). In one of our laboratories, the acute tryptophan depletion (ATD) protocol termed ‘Moja-De’ has been shown to decrease 5-HT release in rodents (20, 21) and to lower tryptophan (TRP) comparably in humans (22), suggesting that this mixture successfully decreases 5-HT synthesis as postulated. While some experiments (23) fail to detect changes in central 5-HT function after ATD, this is the exception rather than the rule in published studies. The author of this comment was also concerned that there would be regional variations in the inhibition of serotonin function. This is logical and consistent with published data on the effects of Moja-De ATD in mice. Mouse studies indicated that depletion of TRP was comparable across different brain areas but that the extent of decrease in 5-HIAA varied by region (20, 21). Regional release of 5-HT is controlled by a combination of cell firing including regionally selective input, the concentration of 5-HT1b receptors on terminals, the amount of tryptophan hydroxylase, and many other factors (24). However, there is no evidence that 5-HT release happens only in selective regions, but we agree the magnitude of ATD effects on release is likely to vary between regions despite comparable depletion of TRP. As regards potential interactions between 5-HT and histamine, we agree that measurement of histidine after depletion of TRP or any other formula lacking HIS is of interest. Young has questioned the results of ATD experiments in which HIS was not included, stating that ‘histidine is an essential amino acid’. However, the essentiality of this amino acid is not clearly established (25). It has been reported that HIS was not necessary for the maintenance of nitrogen balances in short-term (26, 27). Kriengsunyos et al. (28) observed after a long-term histidine depletion administered to healthy adults that there were no effects on the protein metabolism (urinary nitrogen excretion and nitrogen balance). They suggested that the essentiality of this amino acid in healthy adults is still unclear as there are some components that may serve as sources of HIS, although the data they reported indicate that this amount may not be enough for maintain the HIS pool. The other concern expressed by Young was that effects of ATD could reflect disruption of a histamine–serotonin interaction, as ATD would cause a dramatic decrease in histamine synthesis. This is possible, as it is well established that the neurotransmitter histamine is formed from HIS (29), and histamine turnover seems to occur faster than other biogenic amines, such as norepinephrine or 5-HT (30). Therefore, in the absence of HIS, competition from the amino acid mixtures could indeed lower histamine production. However, neither the control nor the ATD mixture in most studies contains histidine, and so histamine would not be differentially affected by the ATD mixture, but should be comparably depleted in both control and ATD mixtures. Nevertheless, it is possible that some interaction between histamine depletion and 5-HT depletion could have behavioral effects. Unfortunately, no behavioral effects of histamine depletion have been clearly established in the literature. A study by Young and his collaborators of HIS depletion effects on sensory and motor behavior in healthy adults (31) showed that HIS in plasma decreased 20% and the ratio HIS/ΣLNAA decreased 59%, but there were no behavioral effects of this depletion. Finally, we disagree with the statement that ‘the relevance of such animal studies to the far more complex human brain is uncertain’. It is well known that validation of translational methods has allowed modeling many aspects of the neuropsychopathology with the use of appropriate animal models, the majority of them throughout the use of rodents (32, 33). Translation of behavioral findings is challenging, due to limits in extrapolating simple behavioral tasks in rodents to sophisticated behaviors in humans. However, biochemical studies of ATD effects in humans and rodents have shown considerable concordance. For example, our studies in humans (5, 22) have been validated in mice (20, 21), consistent with the field as described above (16–19). As Dr. Young points out, detailed anatomic studies of 5-HT synthesis in the human brain are technologically demanding and rarely conducted. However, the concordance between the dependent measures that can be collected in humans (CSF 5-HIAA for example) and comparable measures in rodents (tissue 5-HIAA content, 5-HT and 5-HIAA content in microdialysate) supports the concordance of findings after ATD in humans. In summary, there is convincing and converging evidence that ATD decreases 5-HT synthesis in the brain in both rodents and humans. Interactions between 5-HT and

Effectiveness of Psychotherapy in Adult ADHD: What Do Patients Think? Results of the COMPAS Study:

Objective: In the multicenter study Comparison of Methylphenidate and Psychotherapy in Adult ADHD (COMPAS), the efficacy of treatments has been primarily evaluated by observer-rated symptom change. Here, we additionally analyzed the patients’ subjective evaluation of therapy effects. Method: COMPAS compared ADHD-specific group therapy with unspecific clinical management with/without concomitant pharmacotherapy in a four-armed design. Evaluation through the patients’ retrospective perspective was performed after 1 year (post-treatment) and after another 1.5 years (follow-up). Results: In respect to patients’ subjective ratings, ADHD-specific group psychotherapy outperformed unspecific management post-treatment (z = 4.88, p < .0001) and at follow-up (z = 2.90, p = .004). Rank correlations with rater-based symptom change were small to moderate (post-treatment: rs = 0.28, follow-up: rs = 0.16). Conclusion: Therapy evaluation based on the patients’ perspective supports the concept of ADHD-specific group psychotherapy as a potentially useful therapy option in ADHD.

Cardiovascular and metabolic comorbidities in patients with Alzheimer's disease and vascular dementia compared to a psychiatric control cohort: Comorbidities in patients with dementia

Multimorbidity in dementia is associated with an increased risk of complications and a higher need for care. Having knowledge of cardiovascular and metabolic comorbidities is crucial when making decisions about diagnostic procedures and therapies. We compared the prevalence of comorbidities in hospitalized patients with Alzheimers disease (AD), vascular dementia, and psychiatric diseases other than dementia. Additionally, we compared clinically relevant health‐care indicators (length of hospital stay, rate of re‐hospitalization) between these groups.

P03-130 - Effects of a diminished serotonin synthesis on memory and impulsive aggression in adult ADHD

Introduction Numerous results from investigations including children with ADHD show associations between a diminished serotonin synthesis and memory impairments as well as higher aggression scores. The aim of the present study was the investigation of the association between a diminished serotonin synthesis, logical memory and impulsive aggression in male adult patients with ADHD. Method Twenty male adult patients with ADHD and twenty healthy controls were recruited for this double-blind within subjects crossover study. Subjects completed the Rapid Tryptophan Depletion (RTD) Test or a placebo condition (balanced amino acid load) on either one of two examination days. Clinical variables and general intellectual functioning were assessed. The neuropsychological test battery included the subtest logical memory from the Wechsler Memory Scale (WMS-R), self-assessment of aggression as well as the Point Subtraction Aggression Game (PSAG). Results Statistical analysis revealed significant memory impairments of ADHD patients, which were associated with severity of symptoms in early childhood as well as subjective aggression scores. Effects of the tryptophan depletion were not found, neither for the logical memory subtest nor performance in the PSAG. Conclusions In contrast to previous studies, these findings suggest that the serotonergic system as reflected by the RTD Test has no effect on memory performance or impulsive aggression. However, these results may be due to possible interactions of other catecholamine systems with the serotonergic system that were not controlled in this study. Therefore an additional study is needed to further explore the catecholamine systems and their effects on memory and impulsive aggression.

P01-415 - Association between albumin and social cognition in attention-deficit-hyperactivity-disorder (ADHD)

Introduction Albumin is a protein which serves as a transporter for a variety of metabolites and as a storage for a lot of substances. Although albumin cannot pass the blood-brain-barrier and thus influence the CNS directly, a negative relation between cognitive impairment and serum albumin level has been observed in studies of normal and pathological aging. The aim of the present study was to investigate the association between albumin and social cognition in ADHD. Method 20 adult patients with ADHD and 20 healthy controls participated in a double-blind within subjects crossover study. Participants completed the Moral-Judgment-Test, Tuebingen Affect Battery, the Movie for the Assessment of Social Cognition (MASC) and Cambridge Behaviour Scale (EQ). In addition, ADHD symptoms were assessed by the Wender Utah Rating Scale (WURS-K) and ADHD Self Rating Scale. Serum albumin levels were determined after blood withdrawal. Results In the patient group serum albumin levels were negatively associated with ADHD pathology measured by WURS-K. In addition, a low level of albumin was related with poorer performance in theory of mind, moral judgment competence and affective prosody tasks. Conclusions The results suggest that albumin is related to social cognition in younger patients with ADHD. This is, to the knowledge of the authors, the first investigation, in which the association between albumin and cognition has been investigated in ADHD. Thus the findings of the present study need replication and the neural mechanisms have to be explored in future studies. Further studies are needed to exclude a possible medication effect.