Inhibitory Endophenotypes Help Classify Schizophrenia and Bipolar Patients

Clinicians often misdiagnose mania as schizophrenia while schizophrenia is usually mistaken for schizoaffective disorder. According to a study by Laura F. Martin, MD, of the University of Colorado, and colleagues, physiologic inhibitory endophenotypes may be able to differentiate patients with schizophrenia from patients with bipolar disorder.

The study involved 29 patients with schizophrenia, 40 patients with bipolar disorder, and 18 patients with schizoaffective disorder. The study evaluated suppression of the three biologic indicators of sensory response inhibition, ie, P50 auditory evoked response, leading saccades during smooth pursuit eye movements, and inhibition of saccades during antisaccade tasks. Despite group differences in the electrophysiologic tests, there is a large degree of overlap among individuals from the groups. After logistic regression analysis, results found that P50 ratio and frequency of leading saccades distinguished schizophrenia patients from bipolar patients with a sensitivity of 95% and a specificity of 83%. Participants in the schizoaffective group were split with six patients characterized as schizophrenia-like and 12 patients characterized as bipolar-like.

“I was surprised at how well a combination of only three tests correctly identified so many individuals,” Dr. Martin said.

The biggest limitation to this study was the lack of variety within the sample. The results need to be cross-validated among a different sample of individuals. In addition, it would be helpful to complete the same study in an inpatient group as this study was only completed in an outpatient group with clinically stable disease.

“I would have liked to see if the electrophysiology continued to support the clinical nosology,” Dr. Martin said. “With the increasingly complex task of differentiating acute psychotic mania from shizophrenia, would the area under the receiver operating characteristic curve also decrease?”

While identifying endophenotypes may help clinicians understand genetic studies and the neurobiology of these disorders, this study’s results do not have direct clinical applicability. However, this knowledge may help determine how affective features associated with schizophrenia and psychotic features associated with bipolar disorder make them clearly distinguishable disorders.

Funding for this research was provided by the Veterans Affairs Research Service and the National Institute of Mental Health. (Am J Psychiatry. 2007;164(12):1900-1906.) —ML


Increased Risk of PTSD Symptoms in Combat-Exposed Military Personnel

Soldiers returning from war have long been reported to exhibit symptoms of posttraumatic stress disorder (PTSD). Historically, the prevalence rate of PTSD in military cohorts seems to have corresponded with the level of “boots on the ground” combat. According to previous reports, for example, as many as 30% of returning United States soldiers who fought in the Vietnam War, and 10% of soldiers in the 1991 Gulf War, exhibited PTSD symptoms.

Past studies of PTSD in this population have been retrospective. However, a recent study by Tyler C. Smith, MS, of the Department of Defense Center for Deployment Health Research at the Naval Health Research Center in San Diego, California, and colleagues, includes pre-deployment baseline data on PTSD symptoms in military personnel along with a comprehensive follow-up analyses.

Baseline data were compiled between July 2001 and June 2003 from a cohort of 70,047 active US military personnel; 50,184 personnel participated in follow up questionnaires administered between June 2004 and February 2006. Using follow up data, the investigators determined the incidence of new-onset PTSD in both deployed and non-deployed military personnel. Outcome measures were based on two levels of data collection, including “sensitive” and “specific” definitions. The “sensitive” definition of PTSD symptoms was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria alone; the “specific” definition included DSM-IV criteria along with a required sum of 50, on a scale of 17–85, on the PTSD checklist–civilian version, a 17-item self-report PTSD measure.

Exposure to combat was a significant incidental factor in this study. During follow up, one survey asked participants whether they had ever been exposed to or witnessed “a person’s death due to war, disaster, or tragic event,” “instances of physical abuse (torture, beating, rape),” or “maimed soldiers or civilians.”

New instances of self-reported PTSD were found in 7.6% to 8.7% of deployed personnel who reported combat exposure, 1.4% to 2.1% of deployers with no combat exposure, and 2.3% to 3.0% of non-deployed personnel. Overall, these data indicate a threefold increase in new-onset PTSD cases from baseline. Subjects who reported PTSD symptoms at baseline were excluded from these analyses.

By the “sensitive” criteria, new-onset PTSD symptoms were reported in 4.9% of Army personnel (the highest reported percentage) and 1.8% in the Air Force (the lowest reported percentage). Deployed personnel across all military branches were more likely to be male, born between 1970–1979, less educated (high school/equivalent or less), and combat specialists. However, new-onset PTSD symptoms were proportionately higher in those who were younger, female, never married or divorced, enlisted, black non-Hispanics, and less education (high school/equivalent or less). The researchers note, however, that higher-educated, older members of this cohort, such as officers or Marines, were more likely to report persisting symptoms at follow up, suggesting a reason for this group’s lower odds of new-onset PTSD symptoms.

Another significant finding of this study includes the data that were collected on problem drinking and smoking status across all military branches and occupations. Those who reported current smoking and problem drinking at baseline also had an increased risk of new-onset PTSD, although smoking and problem drinking were also tied to persistent PTSD symptoms.
Funding for this research was provided by the Department of Defense. (BMJ. 2008;336:366-371.) —LS


Symptom Changes in ADHD Found as Children Grow into Adolescence

Affecting approximately 5% to 10% of children and adolescents worldwide, attention-deficit/hyperactivity disorder (ADHD) is a common, chronic behavioral condition associated with cognitive deficits and diminished academic performance, which is characterized by inattention, impulsivity, and hyperactivity. Although children with ADHD may present more often with symptoms of impulsivity and hyperactivity, adolescents with the disorder may have more cognitive deficits, such as impairments with working memory and inhibition. While ADHD is often studied in children and adolescents separately, there have been few large, longitudinal studies of the prevalence of ADHD in adolescents.

Susan L. Smalley, PhD, of the Semel Institute at the University of California at Los Angeles, and colleagues, evaluated adolescents who participated in the Northern Finland Birth Cohort 1986, which studied 9,432 children from the early fetal period to adolescence (16–18 years of age) for ADHD prevalence. The authors also sought to assess the clinical characteristics of ADHD in the adolescent population as compared to the course of the disorder in childhood.

Among the children studied in the Northern Finland Birth Cohort 1986, 6,622 participants responded to a survey about adolescence and ADHD. Smalley and colleagues identified a subset of 457 adolescents among those who responded; this subset included adolescents who may have ADHD and other psychiatric conditions as well as those who did not have the disorder and could act as controls. The authors used a standard screening survey and diagnostic criteria to identify adolescents with ADHD and comorbid disorders.

Smalley and colleagues found that the estimated prevalence of ADHD among adolescents in the birth cohort was 8.5%. They also found that as children with ADHD age, hyperactivity and impulsivity related to the disorder decrease while inattention increases. Most adolescents with ADHD exhibited the inattentive subtype (64%), while the hyperactive-impulsive (8%) and combined (28%) subtypes were found in fewer adolescents.

The study also found that ADHD in adolescence is significantly associated with increased rates of other psychiatric conditions including depression and anxiety disorders. In addition, conduct disorders, such as vandalism and truancy, oppositional behavior, and posttraumatic stress disorder were elevated in adolescents with ADHD as compared to those without the disorder. A lifetime diagnosis of ADHD had a prevalence of 18.2%, and a lifetime diagnosis was also significantly associated with the presence of anxiety and disruptive behavioral disorders.

The authors concluded that although cognitive deficits are present in adolescents with ADHD, they are often not used as an indicator for the disorder in childhood as children with cognitive deficits typically do not show increased symptoms of hyperactivity or inattention, which are symptoms used to identify the disorder in children. Thus, Smalley and colleagues suggest that researchers examine more closely what environmental conditions lead to impairment in children and adolescents with ADHD. 

Regarding medication use to treat the disorder, the authors conclude that researchers should also examine the efficacy of stimulant use in the United States as medication use in Finland was limited and the presentation of ADHD in adolescence was similar to the presentation of the disorder among patients in the US. Although medications are beneficial in the short term, the authors suggest that further study into the long-term course of ADHD and its overall effects is needed.

Funding for this research was provided by the National Institute of Mental Health, the Juselius Foundation, and the Academy of Finland. (J Am Acad Child Adolesc Psychiatry. 2007;46(12):1575-1583.) —CP


Cognitive and Genotypic Predictors of Impulsive Behavior in Alcoholism

The etiology and development of addictive disorders might imply a more serious neurobiologic effect than previously believed, according to a recent study that analyzed the immediate reward bias in the human brain. Using a combination of imaging and genotyping analyses, Charlotte A. Boettiger, PhD, and colleagues at the University of California, San Francisco’s Gallo Clinic and Research Center examined the reaction of several brain regions in recovering, abstinent alcoholics and in subjects with no history of substance abuse.
“Our data suggest possible brain mechanisms for decision-making impairment among alcoholics, which provides an endophenotype and thus an intermediate therapeutic target for testing clinical interventions prior to clinical trials,” Dr. Boettiger said. 

A pronounced bias toward immediate gratification, compared to choosing greater benefits derived over a longer term, is characteristic of people with alcoholism and addictive disorder. Nine recovering, abstinent alcoholics and 10 subjects with no history of substance abuse underwent functional magnetic resonance imaging (fMRI) bold oxygen level-dependent (BOLD) analysis. Subjects were asked to consider hypothetical scenarios in which a lesser award, or a greater, long-term award, was available. fMRI BOLD was conducted during the decision-making process at sites within the posterior parietal cortex, the dorsal prefrontal cortex, and the rostral parahippocampal gyrus regions.

The recovering alcoholic subgroup chose the immediate gratification option three times more often than the control group, and they showed diminished orbital frontal cortex activity—a region of the brain that Dr. Boettiger suggests may be associated with the long-term award. High activity in the dorsal prefrontal cortex and the parietal cortex was associated with a bias toward immediately gratification, which, as Dr. Boettiger explains, “runs counter to the belief that addicts make such choices due to heightened reward sensitivity and suggests that abnormalities in cognitive processing contribute to immediate reward bias.”

This investigation also included a genotyping aspect. Genotype at the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene predicted impulsive behavior and correlated with high activity in the posterior parietal cortex and the dorsal prefrontal cortex. Boettiger and colleagues noted that the data indicate that COMT genotype confers behavioral differences which may be relevant for therapeutic response to specific treatments for substance abuse.

“Behavioral addiction treatment often focuses on learning to think more concretely about the consequences of relapse,” Dr. Boettiger added, “suggesting that stronger mental representations of long-term consequences enables more future-oriented decisions. Our results point to the lateral orbitofrontal cortex as a possible key site for such representations, and support identifying addiction therapies that strengthen orbitofrontal cortex activity during decision making.”

Funding for this research was provided by the Department of Defense and the Wheeler Center for the Neurobiology of Addiction. (J Neurosci. 2007;27(52):14383-14391.) –LS


Sleep Medications Often Denied to Insomnia Patients with Anxiety and Depression

Approximately 20% of the United States population has sleep problems, and every one out of 10 patients experiences chronic insomnia. Patients with insomnia usually endure other comorbidities such as depression and anxiety. According to a study by Rajesh Balkrishnan, PhD, of Ohio State University, and colleagues, patients who suffer from both insomnia and mental health disorders are denied sleep medication more often than those without mental health diagnoses.

The study involved a retrospective data analysis of the National Ambulatory Medical Care Survey. It recorded 5,487 physician visits by patients with insomnia between 1995 and 2004, a sample calculated to represent 161.4 million US patients. Approximately 38% of those surveyed were diagnosed with at least one other condition, including anxiety, episodic mood disorders, high blood pressure, depression, and diabetes. Patients with both insomnia and mental health disorders were 36% less likely to receive pharmacotherapy for insomnia while anxiety patients were 45% less likely. These results reveal that patients with these comorbid disorders are the lowest candidates for sleep medication. In addition, the findings suggest that physicians are tentative to prescribe sleep aids due to these patients’ higher risk of dependence and abuse, a groundless assumption that could lead to worsened mental health conditions.

Funding for this research was provided by a grant from sanofi-aventis. (J Med Econ. 2008;11(1):41-56.) –ML

Dispatches is written by Michelisa Lanche, Carlos Perkins, Jr., and Lonnie Stoltzfoos.