Top Research Findings That Can Change Clinical Practice

Psychiatric TimesPsychiatric Times Vol 29 No 9
Volume 29
Issue 9

Four studies sprang from the TORDIA trial on treatment-resistant depression in children and adolescents and showed that several factors influence treatment efficacy following treatment resistance.

Psychiatrists and other clinical providers are under increasing pressure to stay current. With the fast growth of knowledge, the challenge to keep up with the ever-growing body of information is greater than ever. There is an emerging realization that, as clinical providers, we need help in sorting and evaluating the quality of information before we can apply it to clinical practice. Otherwise, when facing the overload of information we tend to take the first or the most easily accessed without taking into account the quality of the information. As a result, quality of care suffers and costs millions of dollars annually in problems associated with underuse, overuse, and misuse. We need an efficient and effective system of how to sort, evaluate, and use information.

In an effort to sort and evaluate published research that is ready for clinical practice, we undertook a 3-step process:

• We searched the literature published between June 1, 2010 and May 31, 2011 for relevant study findings.

• We asked various psychiatric groups and colleagues the following question: Of the research published from June 1, 2010 through May 31, 2011, which had the most impact on the clinical practice of psychiatry?

• We looked for appraisals in post-publication reviews such as Faculty of 1000 Factor, Evidence-Based Mental Health, commentaries in peer-reviewed journals, etc.

The papers were chosen based on our judgment of their clinical relevance/applicability, ie, their “clinical readiness.” Here we present summaries of the “top” papers that were chosen (the order in which the articles appear is arbitrary). The abstracts are available on PubMed, and many have full text available online.

TreatmentBlader JC, Pliszka SR, Jensen PS, et al. Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. Pediatrics. 2010;126:e796-e806.
A total of 65 preadolescent children with treatment-resistant ADHD and marked aggressiveness were given systematic stimulant treatment. Often this population ends up with adjunctive antipsychotic medication. This study found that approximately 50% of these children would show remission of ADHD symptoms and aggressiveness with the use of higher doses of stimulants than are frequently used in primary care. Among children whose aggressive behavior developed in the context of ADHD and who had insufficient response to previous stimulant treatment in routine clinical care, systematic, well-monitored titration of stimulant monotherapy affected the course of both ADHD and associated aggression. If primary care physicians were comfortable in using higher doses of stimulants to treat nonresponsive aggressiveness, the use of antipsychotics to reduce aggression in preadolescents would be substantially reduced.

Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167:942-948.
In a randomized, double-blind trial, 73 patients with MDD who did not respond to SSRI treatments were randomly assigned to a placebo group or to an augmentation group of SAMe (1600 mg/d) for 6 weeks. Both groups were maintained on stable doses of the SSRIs they were already taking. Intent-to-treat analysis of Hamilton Depression Rating Scale (HAM-D) changes compared the two groups on percentage who had symptom remission and percentage who had at least a 50% reduction on the HAM-D score.

There were no differences in the number of adverse effects or patients who discontinued because of lack of efficacy. Almost 36% of patients in the SAMe augmentation group had symptom remission compared with 12% in the placebo group, resulting in a number needed to treat (NNT) of 4.2. More than 46% in the SAMe group showed greater than 50% improvement compared with 18% in the placebo group (NNT = 3.5). While requiring replication and extension for longer treatment durations and follow-up, the size of the effect of SAMe augmentation seems clinically significant, especially when compared with FDA-approved augmenting agents aripiprazole and olanzapine.

Emslie GJ, Mayes T, Porta G, et al. Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. Am J Psychiatry. 2010;167:782-791.
This is 1 of 4 articles that report outcomes of the TORDIA trial. This trial was made up of 334 children and adolescents aged 12 to 18 years with treatment-resistant depression. They were randomized to 1 of 4 initial treatment arms: an SSRI different from the one that had failed; venlafaxine; a different SSRI plus cognitive-behavioral therapy (CBT); or venlafaxine plus CBT. Ratings of treatment outcomes were double-blind. After 12 weeks, responders were maintained on the same treatment for another 12 weeks. Nonresponders were unblinded as to antidepressant, and treatments could be switched to different medications and/or CBT or augmenting agents could be added. Remission and relapse rates at the end of 24 weeks did not differ between treatments. Despite selection for treatment resistance, 39% of patients achieved remission after 6 months of treatment. Nonresponders had some improvement during the first 6 weeks but seemed to plateau; responders continued to improve throughout the 24-week trial.

Generally, early response predicted remission. Responders had close to a 50% reduction in symptom severity scores by the end of 6 weeks, while nonresponders had improved by only 25%. Among nonresponders, augmenting treatment within the first 12 weeks facilitated remission, while augmentation within the last 12 weeks did not. Other baseline and week-12 variables, including lower severity of symptoms, low family conflict, and the absence of substance abuse, were found to predict remission. Twenty percent of those who had symptom remission by week 12 relapsed by week 24. The importance of recognizing nonresponders during the first 6 weeks and augmenting treatment early is emphasized.

Vitiello B, Emslie G, Clarke G, et al. Long-term outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor treatment: a follow-up study of the TORDIA sample. J Clin Psychiatry. 2011;72:388-396.
The second paper by the TORDIA group presented follow-up data from 48 and 72 weeks after the trial started. Usual community care began after the initial 24-week trial. Remission rates continued to improve, reaching more than 60% after 72 weeks. For responders, symptom levels continued to drop over the entire 72-week period, while for nonresponders symptom level improvements had essentially stopped by 6 weeks. Findings from long-term follow-up reinforce the importance of treatment response during the first 6 weeks and not waiting to initiate treatment augmentation or change, especially if previous treatment resistance has been shown.

Sakolsky DJ, Perel JM, Emslie GJ, et al. Antidepressant exposure as a predictor of clinical outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) study. J Clin Psychopharmacol. 2011;31:92-97.
In this TORDIA follow-on trial, the data came from the same 334 adolescents with SSRI-resistant MDD who were randomized to venlafaxine with or without CBT augmentation or a different SSRI with or without CBT augmentation. All participants received family psychoeducation and supportive management. At weeks 6 and 12, blood levels of the medication and major metabolites were measured in all groups to test whether the extent of response to treatment was related to these blood levels. Dosages were increased for patients who had not improved. Results were mixed in that patients whose medication was switched to citalopram or fluoxetine who had higher plasma levels at 6 weeks were more likely to have improved by 12 weeks, while no such relationship was seen with venlafaxine, paroxetine, or sertraline. This may have been because plasma levels for these latter medications were relatively higher at 6 weeks so that there was something akin to a ceiling effect.

This is the first study that showed a relationship between plasma levels and treatment response in adolescent depression and suggests that plasma levels, particularly for citalopram and fluoxetine, will help decide whether a switch to another SSRI or a dosage increase should be tried.

Shamseddeen W, Asarnow JR, Clarke G, et al. Impact of physical and sexual abuse on treatment response in the Treatment of Resistant Depression in Adolescent Study (TORDIA). J Am Acad Child Adolesc Psychiatry. 2011;50:293-301.
In this TORDIA trial, the original 334 participants were randomly assigned to 4 groups: 2 groups received a different SSRI, and 2 received the SNRI venlafaxine. One group of each medication received additional CBT. In the 12-week study, participants in each treatment group with a history of sexual or physical abuse were compared with group members who had no such history.

The groups that received additional CBT showed greater treatment response (62.8%) than the pharmacotherapy-alone groups (37.6%), but only for patients with no reported history of abuse. In patients with histories of physical abuse, those who received the combination of pharmacotherapy plus CBT had lower response rates (18.4%) than those who received pharmacotherapy alone (52.4%), while histories of sexual abuse had no differential effect on response rates (48.3% and 42.3%, respectively).

These findings suggest that until the mechanisms of effects of physical and sexual abuse are better understood, alternatives to CBT augmentation of antidepressants for adolescents with treatment-resistant depression should be considered when there is a history of physical abuse. On the other hand, CBT augmentation should be considered for adolescents with treatment-resistant depression who do not have a history of abuse.

PrognosisFoti DJ, Kotov R, Guey LT, Bromet EJ. Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization. Am J Psychiatry. 2010;167: 987-993.
This is a report of a cohort study that followed 229 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder within 6 months of their first hospitalization. Their use of cannabis (1 month or 6 month use) and their positive (Scale for the Assessment of Positive Symptoms) and negative (Scale for the Assessment of Negative Symptoms) symptom levels were monitored at baseline and 6 months, and 2, 4, and 10 years later. SCID (Structured Clinical Interview) and GAF (Global Assessment of Functioning) data were also obtained.

At the 10-year assessment, 82% of participants (188) provided at least partial data. At baseline 62% of patients had a history of cannabis use, although only 10% had used cannabis within the month preceding baseline. While the subset of users changed from one assessment point to another, the numbers of cannabis users at each assessment point were between 10% and 18%. At each point, those who had used preceding the assessment showed higher levels of psychotic symptoms than those who had not used, although only the positive psychotic symptom subscale levels were predicted at statistical significance in a multiple regression.

Use of cannabis before the first hospitalization was associated with an earlier age of symptom onset. Use of cannabis after hospitalization was associated with higher psychotic symptom levels. Educating patients and family members about the potential positive effects of reducing cannabis use on psychotic symptoms and helping patients with schizophrenia develop strategies to avoid cannabis use is indicated for a better prognosis.

PreventionRapee RM, Kennedy SJ, Ingram M, et al. Altering the trajectory of anxiety in at-risk young children. Am J Psychiatry. 2010;167: 1518-1525.
Prevention is such an appealing concept, particularly when thinking about preventing the development of potentially lifelong disorders in children. Rapee and colleagues provide compelling evidence that brief intervention (6-session parent training) to reduce overprotection of their behaviorally inhibited children, reduced the incidence of anxiety disorders in their children over a 3-year follow-up period. The randomized controlled trial (n = 73 in both intervention and monitoring control group), utilized scores above 30 on the approach subscale of the Short Temperament Scale for Children, completed by mothers of preschool children, to indicate social withdrawal in their children.

The mother and child pairs were then exposed to various social interaction opportunities in a laboratory setting. Children who tended to avoid social interaction with strangers, another child, and with lab assistants were randomized to either the brief intervention group or a monitoring-only group. Blind diagnostic assessment interviews were conducted to establish baseline disorders and their severity. In the brief intervention group, 6 sets of parents were given 6, 90-minute parenting sessions that covered the nature of anxiety, parent management techniques, the role of over-protection in fostering anxiety, cognitive restructuring of the parents’ anxieties, and training in exposure hierarchies. The training was completed over a 10-week period.

Both groups showed declines in the number of children with diagnosable anxiety disorders and in the severity of anxiety symptoms, although the parent training groups showed significantly fewer children with anxiety disorders and a greater reduction in symptom severity. The intervention was flexible in that it could be developed in schools, community settings, or in practice settings, and the size of the prevention effect grew over the 3-year follow-up period.

Wickramaratne P, Gameroff MJ, Pilowsky DJ, et al. Children of depressed mothers 1 year after remission of maternal depression: findings from the STAR*D-Child study. Am J Psychiatry. 2011;168: 593-602.
This study extends previous findings that treating depressed mothers to remission reduces or prevents psychiatric symptoms in their children. The response to citalopram treatment of depressed mothers who participated in the STAR*D study was evaluated in 80 children. The child’s symptoms were assessed every 3 months for 1 year after symptom remission in the mother, or for 2 years if there was no symptom remission.

Children of mothers with quick (0-3 months, n = 36), slow (3-12 months, n = 28), or no (n = 16) symptom remission were compared for changes in their symptoms or probability of developing symptoms. Children of mothers whose depression symptoms remitted quickly were the most likely to show reductions in symptoms or to avoid the development of new symptoms. Children of mothers whose depression never remitted were more likely to show increases in symptoms, particularly externalizing symptoms, and to develop new symptoms. Children of mothers whose depression remitted slowly were less likely to develop new symptoms and more likely to improve than children of non-remitters, but more likely to develop new symptoms and less likely to improve than children of quick remitters.

This reinforces the importance of treating the parents of depressed children, and treating depressed parents to remission to prevent increases in their child’s symptoms and the development of new ones.

Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry. 2010;167:934-941.
Patients treated with antidepressant medications to remission for MDD (224), panic disorder (75), or bipolar disorders (I, 37; II, 62) were followed for 12 to 100 months after they elected to discontinue their medications. The patients who chose to discontinue their medications in a week or less were compared with those who discontinued over at least a 2-week period. The quickly discontinued group showed significantly higher rates of symptom recurrence after shorter periods of time than the group who discontinued more slowly. While there are design flaws that weaken the findings, this adds to the growing evidence that rapid discontinuation makes symptom return more likely in general, and specifically for depressive symptoms. Patient counseling to avoid rapid discontinuation may serve to extend the duration of symptom remission or improvement.

Large M, Sharma S, Compton MT, et al. Cannabis use and earlier onset of psychosis: a systematic meta-analysis.Arch Gen Psychiatry. 2011;68:555-561.
This meta-analysis included 83 studies (substance users = 8167; nonsubstance users = 14,352) that examined the relationship between drug and alcohol use and age of onset of psychotic disorders. Several studies had demonstrated a relationship between cannabis use and earlier psychiatric hospital admission or diagnosis of schizophrenia. This meta-analysis addressed several methodological weaknesses of previous studies, including looking for psychotic symptom onset rather than first diagnosis, comparing cannabis to other psychoactive substances, including nonschizophrenia psychotic diagnoses, and focusing on young onset patients rather than bias connected to older patients who are less likely to use cannabis.

Age of onset of psychotic disorders, including schizophrenia was 2.7 years earlier among cannabis users than patients who had not used cannabis, while there were no differences in age of onset with alcohol use. The principle implication involves the possible beneficial effects of educating the community or at-risk families and individuals of the possible prevention or delay of psychotic disorders if cannabis use is avoided. Prevention or delay of psychosis onset by educating at-risk families or individuals to avoid cannabis use have not yet been demonstrated, however.

Harm reductionHo BC, Andreasen NC, Ziebell S, et al. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68:128-137.
This longitudinal study looked at 211 patients with first episode schizophrenia who were treated with either first and/or second generation antipsychotics. The patients had repeated MRI scans over an average period of 7.2 years (ranging up to 14 years). Brain volume changes were examined in terms of their relationship to informant reports of the duration of illness, symptom severity, the particular type of antipsychotic used, and history of substance abuse. The more exposure to antipsychotic medications, the greater the volume reductions in grey and white matter, except in the putamen. The longer the duration of illness and the more severe the symptoms, the more reductions in brain volume. Only the role of antipsychotic exposure in reducing brain volumes remained after controlling for the other predictors. Both first generation and second generation antipsychotics reduced brain volumes.

As the augmenting uses of antipsychotics grow in treatments of nonpsychotic disorders, particularly in children, the potential reduction of brain volume should encourage the use of alternative augmenting agents, when treatment augmentation is necessary.

Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ. 2010;340:c693.
A large cohort of older women with breast cancer (2430), treated with tamoxifen and a single SSRI were examined for possible competition for cytochrome P450 2D6 (CYP2D6). Tamoxifen is a prodrug that is metabolized by the hepatic cytochrome P450 enzyme system to its clinically active metabolite, endoxifen. Conversion of tamoxifen to endoxifen is predominantly done by the enzyme CYP2D6. Consequently, drugs that inhibit the CYP2D6 enzyme may potentially interfere with the conversion of tamoxifen to its clinically active metabolite. Mortality rates were compared across different SSRIs and the proportion of time these treatments overlapped. Paroxetine was found to be the only SSRI that increased mortality rates, and the longer the overlap between paroxetine and tamoxifen, the higher the mortality rate. Paroxetine should be avoided if possible for women undergoing tamoxifen treatments.

Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry. 2010;197:266-271.
This large Danish epidemiological study compared the incidence of diabetes among 1.5 million people who did not use antipsychotic medications, and among 350,000 people who were exposed to first and/or second generation antipsychotic medications. Danish registers for prescriptions filled at pharmacies, medical disorders, psychiatric disorders, and total population from 1996 through 2005 were linked to produce the comparison cohorts and measured outcomes. Rates of diabetes per 10,000 person years ranged from 27.5 for unexposed people to 78.9 for people exposed to both first and second generation antipsychotics. As the number of prescriptions for antipsychotic medications increased, so did the rate of diabetes. As the number of antipsychotics used simultaneously in polypharmacy increased, the incidence of diabetes increased.

Comparison between different antipsychotics showed incidence rate differences although physician decision making about who to put on which medication may have biased the results. Overall, it is clear that antipsychotics in general, and especially polypharmacy, are associated with increased diabetes risk.

Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. Int Clin Psychopharmacol. 2011;26:130-140.
Studies of sexual dysfunction associated with single antipsychotic use were combined in a meta-analysis. Rates of overall sexual dysfunction for different antipsychotics were compared. Rates of sexual dysfunction between 16% and 27% were found with quetiapine, ziprasidone, aripiprazole, and perphenazine, while rates between 40% and 60% were found for olanzapine, clozapine, risperidone, haloperidol, and thioridazine. This was interpreted as reflecting different levels of prolactin raising effects. Psychiatrists can now include risk of sexual adverse effects when choosing among antipsychotic medications.

Potential to change clinical practice
These studies have the promise of improving clinical care, but require too many assumptions at this point to merit clinical application. Additional studies are needed to eliminate some of the assumptions that must be made. These are more suggestive of future directions and developments than of ways to improve treatment outcomes.

Johnson BA, Ait-Daoud N, Seneviratne C, et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry. 2011;168: 265-275.
Actively drinking alcohol-dependent patients (N = 283) who sought treatment were randomly assigned to ondansetron treatment or to placebo. The patients were stratified on the basis of the type of polymorphism in the regulatory region of their serotonin transporter gene, the long type (LL), the short type (SS), or a combined long and short (LS). Patients were also categorized on the basis of an additional single nucleotide polymorphism  (SNP) T or G at another region of the serotonin transporter gene.  Of primary interest was whether the effects of ondansetron were different as a function of the type of polymorphism. Patients in all groups received CBT. Using intent-to-treat analyses, the long type ondansetron group showed significant reductions in drinking amount and days without drinking compared with placebo. The LS and SS types showed smaller or absent differences between ondansetron and placebo. The additional effects of  the SNP TT increased the advantages of the long type polymorphism. The effects of using ondansetron to reduce alcohol dependence behaviors were greatest with the LL/TT genetic combination. If genetic screening of alcohol dependent patients allowed reliable and timely identification of this combination, these patients could be assigned to ondansetron with significantly positive effects.

Angst J, Cui L, Swendsen J, Rothen S, et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry. 2010;167: 1194-1201.
A 5692 subject subset of the 9282 original National Comorbidity Survey Replication sample included 2 groups: those identified by interview in the original survey to have any lifetime mental disorder, and those systematically chosen without history of mental disorder. The Composite International Diagnostic Interview was used to categorize patients into 4 groups: those with MDD plus mania, those with hypomania, those with subclinical hypomanic symptoms, or those with depression alone. These groups were compared on prevalence, treatment history, comorbid disorders, treatment for manic and for depressive disorders, symptom severity scores, and age of mood disorder onset. The bipolar category showed the lowest prevalence, highest probability of previous treatment, greatest probability of comorbid disorders, the highest symptom severities for both mania and depression, and earliest age of onset.

The next highest in each of these characteristics were those with depression with hypomania, followed by those with depression with subclinical hypomanic symptoms, followed by those with depression alone. These ordered trends were consistent and support the concept of a mood disorder spectrum with depression and bipolar disorders at opposite ends of the spectrum.

The clinical implication is that many patients with MDD have hypomanic and subclinical hypomanic symptoms that are not relevant to current diagnostic categories but suggest that additional diagnostic effort be made to recognize the presence of hypomanic symptom history. When this history is present, consider the addition of mood stabilizers. However, no data are presented that show that adding mood stabilizers to the treatment or maintenance regimens for patients with MDD and subclinical hypomanic symptoms improves treatment outcomes.

De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol. 2010;67:949-956.
Three cerebrospinal fluid derived biomarkers were tested for their capacity to discriminate between participants with a clinical diagnosis of Alzheimer’s disease (AD), participants with mild cognitive impairment (MCI), and normal participants with no cognitive impairments. A diagnostic model that combined beta-amyloid protein 1-42 and phosphorylated tau181 was developed to best discriminate the three training populations and validated against both a population of autopsy confirmed patients with AD (n = 68) and a group of patients with MCI) who were followed for 5 years (n = 57) to gauge conversion to AD. The model identified 94% of the autopsy confirmed AD patients and 100% of the patients with MCI that worsened into AD.

These findings suggest that diagnosis of AD, and discrimination from alternatives, such as pseudo-dementia, will be improved with the use of these biomarkers. Some exceptional clinical settings could find the model useful in providing early information on risk for AD and for stronger confirmation of AD; however, the need for lumbar punctures negates their usefulness in a general clinical setting. Furthermore, distinctions between AD and other types of dementia have not been demonstrated.

Karg K, Burmeister M, Shedden K, Sen S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry. 2011;68:444-454.
In 2003, Caspi and colleagues reported that the serotonin transporter promoter polymorphism (5-HTTLPR) moderates the relationship between stress and depression. They were the first to offer a specific quantitative model for the nature-nurture interaction. Two subsequent meta-analyses concluded that the evidence did not support the presence of this interaction. The current meta-analysis by Karg and colleagues supports the Caspi findings by pointing out that even the larger of the two negative meta-analyses included only 14 of the 56 studies that have assessed the relationship between 5-HTTLPR, stress, and depression. The Karg et al. meta-analysis included all relevant studies that explored the interaction and found that the studies published to date support the hypothesis that 5-HTTLPR moderates the relationship between stress and depression. This lends support to the hypothesis that, rather than stressful life events that occur just before the onset of depression, maltreatment and early childhood adversities in conjunction with 5-HTTLPR polymorphisms increase the likelihood of future depression.. Once questions of how the serotonin transporter gene polymorphism plus early stress histories relate differently to treatment outcomes and relapse, the recognition of this combination might be used to tailor treatment strategies.

Stevenson J, Sonuga-Barke E, McCann D, et al. The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children’s ADHD symptoms. Am J Psychiatry. 2010;167:1108-1115.
This study links the effect of food additives and ADHD symptoms on a genetic level. The findings indicate a link between histamine and ADHD symptoms, with polymorphisms in the HNMT gene-moderating behavioral responses to food additives. In a double-blind, placebo-controlled crossover trial, an aggregate ADHD symptom measure was the main outcome variable. Children aged 3 years (n = 153) and 8/9 years (n = 144) were given a fruit drink with 2 food color additives and sodium benzoate (preservative) in the drink.

The adverse effect of food additives on ADHD symptoms was moderated by histamine degradation gene polymorphisms HNMT T939C and HNMT Thr105Ile in 3- and 8/9-year-old children and by a DAT1 polymorphism (short versus long) in 8/9-year-old children only. The authors concluded that histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistencies in previous studies. The study explains the frequent claim that food allergy/intolerance is a cause of ADHD symptoms and the effects of infections in aggravating aberrant behavior. It supports a potential target for therapeutic intervention in ADHD focused on the H3 receptor. It shows that histamine release and its effects on the CNS may play a crucial role in mediating the effects of artificial food colors on ADHD symptoms.

These findings may indicate that dietary modifications can have some effect on hyperactivity and distractibility in children with ADHD. This important confirmation of the effects of food dyes has potential implications for identifying the connections between genetic deficits in histamine metabolism and symptoms consistent with ADHD. The lack of connection to classic dopamine-based genetic variants creates an entirely new category of ADHD that may explain many of the atypical cases and potentially the otherwise challenging to understand “adult onset” ADHD-like presentations. Identifying the subgroup of children with the histamine degradation gene polymorphism will allow more targeted dietary interventions with a higher likelihood of positive outcomes.

Others would very likely choose different reports to include or exclude, so that the notion that these are definitively the “top” papers cannot be defended. However, these are papers of high quality with direct clinical application. This view of clinical research also provides insight into highly dynamic areas of clinical investigations, which again can be hidden by the mass of studies available. For example, many of the papers included here were on child and adolescent disorders. The percentage of papers included in this sample on child and adolescent disorders far exceeds the percentage of total psychiatric research papers on child and adolescent disorders. This suggests that research on child and adolescent disorders is producing a relatively high level of clinically applicable findings, which could have policy, funding, and hiring implications. The papers on cannabis also suggest this area of research is producing useful and implementable clinical changes. At the same time, implementable clinical changes related to genetic and biological markers seem to be getting closer on disorders ranging from depression to ADHD.

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