• Medications used to treat attention-deficit/hyperactivity disorder (ADHD) are associated with a small increase in the risk of psychosis or mania, according to an analysis conducted by Food and Drug Administration (FDA) reviewers and published in the February Pediatrics.

From 2005 to 2006, the FDA conducted a comprehensive review of data from 49 randomized, controlled clinical trials that were submitted by manufacturers. The agency reviewers compared the rates of psychiatric adverse events between pediatric ADHD patients who took active drugs and patients who took placebo. The drugs included in the evaluation were various formulations of methylphenidate and dexmethylphenidate, atomoxetine, and modafinil; modafinil was studied, although it is not approved to treat ADHD.

After pooling these trials, the reviewers identified 11 events of psychosis or mania in patients exposed to active drugs during the double-blind treatment periods, compared with no such events in subjects exposed to placebo. The average rate of the adverse event was 1.48 per 100 persons in a year. Spontaneous postmarketing safety surveillance identified 865 case reports of psychosis, mania, or similar events. The most common symptoms of hallucinations related to ADHD drugs in children were “visual and/or tactile sensations of insects, snakes, or worms.”

Mosholder AD, et al. Hallucinations and Other Psychotic Symptoms Associated With the Use of Attention-Deficit/Hyperactivity Disorder Drugs in Children.Pediatrics. 2009; 123(2):611-6.

• Guanfacine extended release was more effective than placebo in treating children and adolescents with ADHD in a randomized, double-blind, controlled trial. A total of 324 ADHD patients aged 6 to 17 were randomly assigned to receive placebo or guanfacine, 1 mg, 2 mg, 3 mg, or 4 mg a day for nine weeks. Patients on active guanfacine saw significant reduction from baseline in ADHD symptoms, which was measured by the ADHD Rating Scale-IV, in all four dose groups. The reduction in each of the guanfacine groups was significantly greater than in the placebo group. Notably, the weight-adjusted dosage correlated with response.

Because guanfacine is an α_2A receptor agonist, lowered blood pressure was an expected side effect. The mean systolic blood pressure was reduced by 7.39 mmHg from baseline and the mean diastolic blood pressure by 5.43 mmHg in the guanfacine 4 mg group at weeks 4 to 6. The mean heart rate was reduced by 9.51 beats a minute in the same dose group. The most common adverse effects were drowsiness and sleepiness, headache, fatigue, dizziness, irritability, upper abdominal pain, and nausea.

The study was funded by Shire. Guanfacine extended release has not been officially approved by the FDA to treat ADHD, although the agency issued an approvable letter to Shire in 2007.

Sallee FR, et al. Guanfacine Extended Release in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled Trial.J Am Acad Child Adolesc Psychiatry. 2009; 48(2):155-65.

• Known risk factors of Alzheimer's disease (AD) and dementia, such as impaired cognitive function, older age, and carrying the apolipoprotein E (APOE) 4 allele, were found to be associated with particular characteristics on a positron emission tomography (PET) scan of the brain using a radioactive labeling agent known as FDDNP. This agent, which contains a radioactive fluoride isotope, binds to amyloid plaques and tau protein tangles, which accumulate in the brain of patients who develop Alzheimer's.

In this study, 76 healthy volunteers who were aged 47 to 87 and did not have dementia, underwent PET brain scans after receiving intravenous injections of FDDNP. About half of the subjects had mild cognitive impairment, and half were APOE-4 allele carriers. The researchers saw increased binding by FDDNP in the various brain regions of subjects who had cognitive impairment, who were older, and who carried APOE-4.

The study was conducted at the University of California at Los Angeles, which holds the patent on FDDNP. It was funded by grants from the National Institutes of Health, the Department of Energy, the Rotary CART Fund, and several other foundations. Siemens has licensed the molecule and has filed an investigational new drug application with the FDA (Psychiatric News, October 5, 2007).

Small GW, et al. Influence of Cognitive Status, Age, and APOE-4 Genetic Risk on Brain FDDNP Positron Emission Tomography Imaging in Persons Without Dementia. Arch Gen Psychiatry. 2009; 66(1):81-7.

• Galantamine showed efficacy in improving cognitive function in elderly patients with severe Alzheimer's, but did not significantly improve other aspects of overall activities of daily living. In a randomized, double-blind, placebo-controlled study, 207 patients with severe Alzheimer's were given galantamine, and 200 took placebo. Galantamine is approved by the FDA for treating mild and moderate Alzheimer's.

After 26 weeks, the patients' cognitive function, measured by the Severe Impairment Battery scores, improved in the galantamine group, which was significantly different from the deterioration observed in the placebo group. However, the change in mean scores on the minimum data set–activity of daily living scale did not significantly differ between the two groups. The adverse events were similar between the galantamine and placebo groups.

The patients in this study had a mean age of 84 and resided in nursing homes. The study was funded by Janssen-Cilag, the Belgium-based branch of Johnson and Johnson.

Burns A, et al. Safety and Efficacy of Galantamine (Reminyl) in Severe Alzheimer's Disease (The SERAD Study): A Randomized, Placebo-Controlled, Double-Blind Trial. Lancet Neurol . 2009; 8(1):39-47.

• In a meta-analysis, three authors from the World Health Organization's Collaborating Centre for Research and the University of Verona, Italy, found that exposure to selective serotonin reuptake inhibitors (SSRIs) was associated with a decreased likelihood of attempted and completed suicide in adults and the elderly compared with no SSRI exposure. However, SSRI exposure was associated with an increased likelihood of attempted and completed suicide in younger people.

The data were pooled from eight observational cohort or case-control studies that reported suicides and previous SSRI exposure in patients with a diagnosis of major depression who attempted or completed suicide. Five of the studies included children and adolescents aged 2 to 18, seven studies included adults aged 18 to 64 years, and two of the studies included adults 65 years or older. The odds ratio for completed and attempted suicide (not including suicidal thoughts or preparatory acts for suicide) associated with SSRI exposure was 1.92 in the age 6 to 18 group, 0.57 in the adult group, and 0.46 in the elderly group. All three risk ratios were statistically significant.

The study authors and an accompanying editorial both noted that the analysis of studies with naturalistic design has numerous inherent limitations for drawing conclusions. For example, the study did not have enough data to adjust for the severity of depression in adolescents receiving SSRIs, which might be collectively more severe than adults being prescribed SSRIs. The editorial urged that randomized, controlled trials be conducted to answer many remaining questions about the true risk of SSRIs on adolescent suicide.

Barbui C, et al. Selective Serotonin Reuptake Inhibitors and Risk of Suicide: A Systematic Review of Observational Studies.CMAJ. 2009; 180(3):291-7.

Gibbons R and Mann JJ. Proper Studies of Selective Serotonin Reuptake Inhibitors Are Needed for Youth With Depression.CMAJ. 2009; 180(3):270-1.

• A randomized, double-blind, placebo-controlled trial showed that older patients suffering from generalized anxiety disorder (GAD) can obtain some benefits from escitalopram, but the effect is fairly modest compared with placebo. Among the 177 patients with GAD and aged 60 or older, 82 were given 10 mg to 20 mg of escitalopram a day and 92 took placebo. After 12 weeks of treatment, the escitalopram group had a statistically significantly higher cumulative response rate than the placebo group (69 percent versus 51 percent, respectively). The anxiety symptoms and self-reported role functioning were also significantly improved in the escitalopram group compared with the placebo group. However, a more conservative intention-to-treat analysis on the response rates did not reach statistical significance between the groups.

Escitalopram was relatively well tolerated in these older adults. The dropout rate due to adverse effects of the drug was 3 percent. The most common adverse effects reported by patients were fatigue or somnolence, sleep disturbance, and urinary symptoms, which, the authors noted, were different from the risk profiles reported by younger patients or older patients with major depressive disorder taking escitalopram.

The study was funded by grants from the National Institutes of Health, Center for Mental Health Services Research, the Advanced Center for Interventions and Services Research in Late-Life Mood Disorders, the John A. Hartford Center of Excellence in Geriatric Psychiatry, and the University of Pittsburgh Medical Center endowment in geriatric psychiatry. The maker of escitalopram, Forest Laboratories, provided free medication for the study.

Lenze EJ, et al. Escitalopram for Older Adults With Generalized Anxiety Disorder: A Randomized Controlled Trial.JAMA. 2009; 301(3):295-303.

• The effectiveness of 12-week olanzapine treatment did not differ significantly from that of placebo for patients with borderline personality disorder in a randomized, double-blind, placebo-controlled clinical trial funded by Eli Lilly. A total of 314 subjects with borderline personality disorder were randomly assigned to take either olanzapine or placebo. Patients' symptoms, measured by the Zanarini Rating Scale for Borderline Personality Disorder, improved substantially from baseline in both the olanzapine and the placebo group, but the difference was not statistically significant. The mean dose of olanzapine in the treatment period was 7 mg a day.

The olanzapine group had significantly greater average weight gain and a higher rate of abnormally high prolactin levels than the placebo group.

Schulz SC, et al. Olanzapine for the Treatment of Borderline Personality Disorder: Variable Dose 12-Week Randomized Double-Blind Placebo-Controlled Study.Br J Psych. 2008; 193(6):485-92. ▪