• A meta-analysis of published studies in the June 17 Journal of the American Medical Association found no evidence that variations in the serotonin transporter gene (5-HTTLPR) interact with stressful life events to increase the risk of depression. A number of studies were conducted after Avshalom Caspi, Ph.D., and colleagues published a study in the July 18, 2003, Science that identified a significant interaction between stressful life events and a specific genetic variation in the promoter region of 5-HTTLPR (long or short form) in the emergence of depression. This meta-analysis pooled data from 14 published studies of the association between 5-HTTLPR genotypes or stressful life events and diagnosed depression. The study authors pooled data from more than 14,000 subjects, among whom 1,769 had depression. They found no significant association between the 5-HTTLPR genotype and depression, nor did the genotype interact with stressful life events to significantly increase the risk of depression. The number of stressful life events, however, was associated with depression.

The slow progress of searching for genetic causes of psychiatric disorders has frustrated the field, the authors said, largely because of an imperfect classification system, a lack of clear diagnostic markers, and poorly defined etiologies. Meanwhile, individual genetic variations appear to have very modest effects on psychiatric disorders or vulnerabilities to them; therefore, each gene's effect is difficult to detect and replicate. Despite the allure of simple answers, the authors noted, "it is critical that health practitioners and scientists recognize the importance of replication of such findings before they can serve as valid indicators . . . or have utility for translation into clinical and public health practice."

Risch N, Herrell R, Lehner T, et al.: Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-Analysis. JAMA. 2009;301(23):2462-2471

• Methylphenidate did not differ significantly from amphetamine salts in the risk of increasing emergency department visits for cardiac reasons among youth with attention-deficit/hyperactivity disorder (ADHD) who are taking stimulants, according to a retrospective study of medical claims data in the Florida Medicaid database from July 1994 to June 2004. Among the 30,576 enrollees aged 3 to 20 who had a diagnosis of ADHD and had received at least one prescription for either methylphenidate or amphetamine, 456 visited the emergency department for cardiac-related reasons including tachycardia, syncope, arrhythmias, hypertension, angina, stroke, aortic or thoracic aneurysm, and acute myocardial infarction.

After controlling for various baseline factors, including congenital abnormalities and concurrent medications, the relative risk was similar between youth who took methylphenidate and those who took amphetamine. The rates of emergency department visits were 10.0 and 9.5 per 1,000 patient-years for youth with use of methylphenidate and amphetamine at the time of the visits, respectively. The rates were 7.2 and 7.6 per 1,000 patient-years for youth with past use of methylphenidate and amphetamine, respectively, before the visits. The study did not include a cohort of youth with no stimulant treatment.

Winterstein AG, Gerhard T, Shuster J, Saidi A: Cardiac Safety of Methylphenidate Versus Amphetamine Salts in the Treatment of ADHD. Pediatrics. 2009; 124(1):75-80

• After being associated with schizophrenia, autism, and Tourette syndrome, DNA copy number variants (CNVs) have recently been linked to ADHD in a study published online in Molecular Psychiatry on June 23. The study compared CNVs in the DNA samples of 335 ADHD patients and their parents and 2,026 unrelated healthy controls and identified 222 inherited CNVs in the patients and parents, but not in the controls. There are no individual CNVs that are overrepresented in the patient/parent ADHD cohort, but more of the rare CNVs seen in this cohort affect candidate genes that have been shown to play a role in neurodevelopment or have been implicated in other neuropsychiatric diseases, including A3BP1, AUTS2, CNTNAP2, and IMMP2L. Four different deletions were found in PTPRD, a gene encoding the protein tyrosine phosphatase and previously implicated in restless legs syndrome. A glutamate receptor gene, GRM5, was affected by a CNV seen in one parent and her three children, all with ADHD symptoms. This gene has been suspected in ADHD in past research.

Elia J, Gai X, Xie HM, et al.: Rare Structural Variants Found in Attention-Deficit/Hyperactivity Disorder Are Preferentially Associated With Neurodevelopmental Genes. Mol Psychiatry advance online publication, June 23, 2009

• A longitudinal case-control study of ADHD suggests that stimulant treatment has a protective effect against depressive and anxiety disorders and other negative outcomes.

A cohort of 140 white male children aged 6 to 17 with ADHD and treated at pediatric and psychiatric clinics was reassessed at one, four, and 10 years after baseline. The study was naturalistic and did not involve active interventions. At the 10-year follow-up, the researchers were able to reassess 112 participants (80 percent) for clinical outcomes. Of the entire cohort, 92 children received stimulant treatment at some point in their lives and 39 did not. Compared with the children who did not have stimulant treatment, those treated with stimulants had statistically significantly lower rates of developing major depressive disorder, anxiety disorder, conduct disorder, and oppositional defiant disorder and were less likely to repeat a grade.

Biederman J, Monuteaux MC, Spencer T, Wilens TE, Faraone SV: Do Stimulants Protect Against Psychiatric Disorders in Youth With ADHD? A 10-Year Follow-Up Study. Pediatrics. 2009;124(1):71-78

• In the United States, excessive alcohol use is a significant contributor to suicide and disproportionally affects certain racial and ethnic minorities. This was the conclusion of an analysis of 2005-2006 suicide data from 17 states conducted by the Centers for Disease Control and Prevention. Nearly 1 of 4 suicide completers (24 percent) who were tested for blood alcohol had a blood alcohol concentration at or above the legal level of intoxication of 0.08 g/dL. This rate of alcohol intoxication was the highest, 37 percent, among American Indians/Alaska Natives, followed by 29 percent among Hispanics, and 24 percent among white, non-Hispanics. The rates were lower in black, non-Hispanics (14 percent) and Asian/Pacific Islanders (12 percent).

When age groups of suicide completers were assessed, the researchers found that more than half (54 percent) of American Indian/Alaska Native suicide victims aged 30 to 39 were intoxicated, the highest rate among all age/ethnic groups. In the overall sample, 25 percent of male decedents and 18 percent of female decedents were intoxicated.

Centers for Disease Control and Prevention: Alcohol and Suicide Among Racial/Ethnic Populations—17 States, 2005-2006. MMWR. 2009;58(23): 637-641

• New Analyses of data from the Treatment for Adolescents With Depression Study (TADS), which was funded by the National Institute of Mental Health, demonstrated that suicidal events in adolescents were associated with persistent, symptomatic depression. Suicidal events were identified using standardized questionnaire and symptom assessments during the study. Suicidal events were defined as suicidal ideation, suicide attempts, or preparatory acts toward an imminent attempt.

Adolescents aged 12 to 17 (n=439) were randomized to fluoxetine, cognitive-behavioral therapy (CBT), a combination of fluoxetine and CBT, or placebo for the first 12 weeks. After 12 weeks, the double blind on treatments was removed, and patients who responded or partially responded to their treatment continued for a total of 36 weeks. After pooling all study patients' clinical data, the authors found that 44 patients (10 percent) had at least one suicidal event during the study, although no patient completed suicide. Baseline severity of self-rated suicidal ideation was significantly associated with the occurrence of suicidal events, as was presence of concurrent depressive symptoms. There was no difference in the timing of the suicidal events between patients treated with antidepressant medication or CBT only. The patients who had at least one suicidal event did not show increased irritability, insomnia, or agitation in the two weeks before the event, but 73 percent of them reported acute interpersonal stressors, such as conflicts with parents or peers, before the event.

Vitiello B, Silva SG, Rohde P, et al.: Suicidal Events in the Treatment for Adolescents With Depression Study (TADS). J Clin Psychiatry. 2009;70(5):741-747

• A genomewide association study comparing the DNA of 1,771 patients with autism with that of 2,538 healthy controls identified rare copy number variants (CNVs) located at more than 150 loci, including both deletions and duplications of DNA chunks. These CNVs were present in the case subjects but not the healthy controls. Some of the identified CNVs affect genes previously linked to autism, such as the NRXN1 and UBE3A genes, while others suggest new candidate genes such as BZRAP1 and MDGA2. The study pointed to many genes and, in turn, diverse physiological pathways that are potentially involved in autism's pathology.

Bucan M, Abrahams BS, Wang K, et al.: Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes. PLoS Genetics. 2009; 5(6):e1000536 ▪