Nadine M. Melhem

Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression: The TORDIA Randomized Controlled Trial

CONTEXT Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy. OBJECTIVE To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006. INTERVENTIONS Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy. MAIN OUTCOME MEASURES Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Childrens Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. RESULTS Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medication switch alone (40.5%; 95% CI, 33%-48%; P = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%-55%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment. CONCLUSIONS For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00018902.

Common genetic variants, acting additively, are a major source of risk for autism.

BackgroundAutism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals.MethodsBy using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status.ResultsBy analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating.ConclusionsOur results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.

The Incidence and Course of Depression in Bereaved Youth 21 Months After the Loss of a Parent to Suicide, Accident, or Sudden Natural Death

OBJECTIVE This study examined effects of bereavement 21 months after a parents death, particularly death by suicide. METHOD The participants were 176 offspring, ages 7-25, of parents who died by suicide, accident, or sudden natural death. They were assessed 9 and 21 months after the death, along with 168 nonbereaved subjects. RESULTS Major depression and alcohol or substance abuse 21 months after the parents death were more common among bereaved youth than among comparison subjects. Offspring with parental suicide or accidental death had higher rates of depression than comparison subjects; those with parental suicide had higher rates of alcohol or substance abuse. Youth with parental suicide had a higher incidence of depression than those bereaved by sudden natural death. Bereavement and a past history of depression increased depression risk in the 9 months following the death, which increased depression risk between 9 and 21 months. Losing a mother, blaming others, low self-esteem, negative coping, and complicated grief were associated with depression in the second year. CONCLUSIONS Youth who lose a parent, especially through suicide, are vulnerable to depression and alcohol or substance abuse during the second year after the loss. Depression risk in the second year is mediated by the increased incidence of depression within the first 9 months. The most propitious time to prevent or attenuate depressive episodes in bereaved youth may be shortly after the parents death. Interventions that target complicated grief and blaming of others may also improve outcomes in symptomatic youth with parental bereavement.

Familial Transmission of Suicidal Behavior

Adoption and twin studies show that familial transmission of suicidal behavior is partly attributable to genetic factors. Transmission of suicidal behavior is mediated by transmission of impulsive aggression or neuroticism and neurocognitive deficits. The most plausible explanations for nongenetic familial transmission are the intergenerational transmission of abuse and adverse familial environments. Bereavement and relationship disruption contribute to suicidal risk via the development of complicated grief, although long-term effects may be mediated by a complex chain of interrelated events. Imitation may contribute to suicidal risk, at least in attempted suicide. However, so-called family environmental factors often are related to risk factors that are heritable. Conversely, genetic factors exert their impact on depression and suicidal behavior via interaction with a stressful environment.

A preliminary longitudinal magnetic resonance imaging study of brain volume and cortical thickness in autism.

BACKGROUND Autism is a developmental neurobiologic disorder associated with structural and functional abnormalities in several brain regions including the cerebral cortex. This longitudinal study examined developmental changes in brain volume and cortical thickness (CT) using magnetic resonance imaging (MRI) in children with autism. METHODS MRI scans and behavioral measures were obtained at baseline and after a 30-month interval in a sample of male subjects with autism (n = 18) and healthy age-, and sex-matched control subjects (n = 16) between ages 8 and 12 years at baseline. RESULTS No differences in brain volumes were observed between the autism and control subjects at baseline or follow-up. However, differences in total gray matter volumes were observed over time with significantly greater decreases in the autism group compared with control subjects. Differences in CT were observed over time with greater decreases in the autism group compared with control subjects in several brain regions including the frontal lobe. When accounting for multiple comparisons, differences between the two groups became nonsignificant except for changes in occipital CT. Furthermore, associations were observed between several clinical features and changes in CT with greater thinning of the cortex being correlated with more severe symptomatology. CONCLUSIONS Findings from this study provide preliminary evidence for age-related changes in gray matter volume and CT in children with autism that are associated with symptoms severity. Future longitudinal studies of larger sample sizes are needed to evaluate developmental changes and examine the relationships between structural abnormalities and clinical expressions of the disorder.

Antecedents and Sequelae of Sudden Parental Death in Offspring and Surviving Caregivers

OBJECTIVES To examine the psychiatric antecedents that put parents at risk for early death, and the psychological sequelae of bereavement in offspring and caregivers. DESIGN A population-based study. SETTING Bereaved families were recruited through the coroners records and by advertisement. Control families were recruited by random-digit dialing and advertisement. PARTICIPANTS Families with biological offspring from 7 to 25 years of age in which 1 parent died of suicide, accident, or sudden natural death were included (n = 140). Controls (n = 99) had 2 living parents and their biological offspring and had no death of a first-degree relative within the past 2 years. MAIN OUTCOME MEASURES Lifetime psychiatric history for deceased parents (probands) and new-onset psychiatric disorders, self-reported symptoms, and functional status in offspring and surviving caregivers. RESULTS Bipolar disorder, substance abuse, and personality disorders are more common in probands who died of suicide or accident than in control parents. Bereaved offspring and their caregivers were at increased risk for depression and posttraumatic stress disorder. Bereaved offspring had a 3-fold (95% confidence interval, 1.3-7.0) increased risk of depression, even after controlling for antecedent and concomitant risk factors. Offspring bereaved by suicide showed similar outcomes compared with those bereaved by other types of death. CONCLUSIONS Bereavement conveys an increased risk of depression and posttraumatic stress disorder above and beyond other vulnerability factors. Better integration of medical and psychiatric care may prevent premature parental death, but once it occurs, physicians should be alert to the increased risk for depression and posttraumatic stress disorder in bereaved offspring and their caregivers.

Association of FKBP5 Polymorphisms With Suicidal Events in the Treatment of Resistant Depression in Adolescents (TORDIA) Study

OBJECTIVE The authors sought to assess the relationship between candidate genes and two clinical outcomes, namely, symptomatic improvement and the occurrence of suicidal events, in a sample of treatment-resistant depressed adolescents. METHOD A subsample of depressed adolescents participating in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial, 155 of whom were of European origin, were genotyped with respect to 21 polymorphisms on 12 genes that have a reported association with depression, treatment response, or suicidal events. Participants had not responded to a previous adequate trial with an antidepressant and were randomized to receive either another selective serotonin reuptake inhibitor or venlafaxine, with or without cognitive-behavioral therapy (CBT). Single-nucleotide polymorphism (SNP) analyses were conducted using PLINK with permutation procedures. RESULTS No relationship was observed between any polymorphism and response to treatment. The FKBP5 (which codes for a protein causing subsensitivity of the glucocorticoid receptor) rs1360780TT and rs3800373GG genotypes were associated with suicidal events (N=18), even after controlling for treatment effects and relevant covariates. These two SNPs were in significant linkage disequilibrium (r=0.91). CONCLUSIONS The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity. These results are consistent with those of other studies linking alterations in the hypothalamic-pituitary-adrenal axis with suicidal behavior. The small number of events and lack of a placebo condition make these results preliminary. Replication with a larger sample and a placebo condition is needed to assess whether these events are related to treatment.

An MRI and proton spectroscopy study of the thalamus in children with autism

Thalamic alterations have been reported in autism, but the relationships between these abnormalities and clinical symptoms, specifically sensory features, have not been elucidated. The goal of this investigation is to combine two neuroimaging methods to examine further the pathophysiology of thalamic anomalies in autism and to identify any association with sensory deficits. Structural MRI and multi-voxel, short echo-time proton magnetic resonance spectroscopy ((1)H MRS) measurements were collected from 18 male children with autism and 16 healthy children. Anatomical measurements of thalamic nuclei and absolute concentration levels of key (1)H MRS metabolites were obtained. Sensory abnormalities were assessed using a sensory profile questionnaire. Lower levels of N-acetylaspartate (NAA), phosphocreatine and creatine, and choline-containing metabolites were observed on the left side in the autism group compared with controls. No differences in thalamic volumes were observed between the two groups. Relationships, although limited, were observed between measures of sensory abnormalities and (1)H MRS metabolites. Findings from this study support the role of the thalamus in the pathophysiology of autism and more specifically in the sensory abnormalities observed in this disorder. Further investigations of this structure are warranted, since it plays an important role in information processing as part of the cortico-thalamo-cortical pathways.

Corpus callosum volume in children with autism.

The corpus callosum (CC) is the main commissure connecting the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. However, most studies examined the mid-sagittal area and investigations applying novel methods are warranted. The goal of this investigation is to apply a volumetric method to examine the size of the CC in autism and to identify any association with clinical features. An MRI-based morphometric study of the total CC volume and its seven subdivisions was conducted and involved 22 children with autism (age range 8.1-12.7 years) and 23 healthy, age-matched controls. Reductions in the total volume of the CC and several of its subdivisions were found in the autism sample. Associations were observed between CC structures and clinical features including social deficits, repetitive behaviors, and sensory abnormalities. Volumetric alterations of the CC observed in this investigation are consistent with midsagittal area tracings of decreased CC size in autism. These findings support the aberrant connectivity hypothesis with possible decrease in interhemispheric communications.

Do common variants play a role in risk for autism? Evidence and theoretical musings

Both rare and common genetic variants underlie risk for almost any complex disease. Over the past few years a common tool for identifying common risk variants is genome-wide association or GWA. Our analyses focus on results from GWA targeting common variants affecting risk for autism spectrum disorders (ASD). Thus far three large GWA studies have been published, each of which highlights a single, non-overlapping risk locus. Evaluation of these studies suggests that combination of their data would diminish evidence for all of these loci, making none of them significant. Despite this paucity of findings, statistical theory can be used to infer a plausible distribution of effect sizes for SNPs affecting risk for ASD. We lay out this theory, calculate plausible distributions, and discuss the results in the context of results from GWA studies for schizophrenia.