Med Check

The size of placebo response in clinical trials of antipsychotic drugs varies by the duration, year of publication, sample size, and other factors, a meta-analysis of 63 randomized, controlled trials revealed. Ofer Agid, M.D., of the University of Toronto and colleagues identified these trials, whose results were published between 1970 and 2009. The extent of placebo response as measured by the Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS) was analyzed. The authors found that more recent studies, studies with shorter duration, studies conducted in community hospitals, and studies involving patients with higher baseline BPRS or PANSS scores reported larger placebo response than older, longer, academically conducted studies and studies enrolling less severely ill patients.

Since the size of placebo response directly affects the detection of drug response as well as the effect size of the drug, the authors suggested that researchers should consider factors that may systematically influence placebo response when they design placebo-controlled studies. This meta-analysis was funded by Pfizer.

An open-label pharmacokinetic study, conducted by Mona Darwish, Ph.D., of Cephalon Inc. and colleagues, showed that concomitant administration of armodafinil and quetiapine appears to result in significant interaction. In this pharmacokinetic study, 25 adult patients diagnosed with schizophrenia took quetiapine alone for several days, and their blood samples were analyzed for the drug's plasma concentrations. They were then given armodafinil and quetiapine on the same day, and blood samples were again analyzed for quetiapine concentrations. The maximum plasma concentration of quetiapine was reduced by 45 percent, and the total drug exposure, measured by area under the time-concentration curve within 24 hours, was reduced by 42 percent when both drugs were taken on the same day.

Cephalon is the maker of armodafinil. In June the company announced that armodafinil had failed a phase 2 clinical trial in which it was tested for effectiveness to treat negative symptoms in schizophrenia. The company will no longer pursue this indication.

The effectiveness and tolerability of paliperidone for the treatment of irritability in adolescents and young adults with autistic disorder are being tested in an ongoing open-label study. Kimberly Stigler, M.D., and colleagues at the Christian Sarkine Autism Treatment Center at Indiana University School of Medicine reported preliminary findings to date. The study included patients aged 12 to 21 with autistic disorder and substantial irritability, defined as having a Clinical Global Impression-Severity (CGI-S) score of at least 4 and an Aberrant Behavior Checklist-Irritability (ABC-I) score of at least 18 at baseline. The patients were given paliperidone 3 mg to 9 mg a day for eight weeks.

Of the first 24 enrolled patients who took at least one dose of paliperidone, 20 (83 percent) achieved clinical response, defined as having a score on the CGI-Improvement scale of 1 or 2 and at least 25 percent improvement from baseline in ABC-I score. The patients' mean body weight increased by 5.1 pounds from baseline, the authors also reported.

The study was funded by Janssen Pharmaceuticals, which makes paliperidone.

The use of aripiprazole in treating irritability in pediatric patients aged 6 to 17 with autistic disorder was studied in an open-label, 52-week clinical trial led by Meeta Patel, Pharm.D., of Bristol-Myers Squibb (BMS). This long-term study enrolled 330 patients, of whom 244 had participated in two previous double-blind, placebo-controlled, eight-week trials on the short-term efficacy of aripiprazole in autism-related irritability; 86 had not participated in prior trials.

Of the 330 patients, 199 completed 52 weeks of treatment. The mean ABC-I score increased by 0.7 points in patients who had received aripiprazole previously, decreased by 6.1 in patients who had received placebo previously, and decreased by 6.5 in patients who had not participated in previous trials. No statistical analysis was reported.

Aripiprazole is approved to treat autism-associated irritability based on the above two short-term studies, but its long-term use for this indication has not been approved. The study was funded by BMS and Otsuka Pharmaceutical, which co-own aripiprazole.

A large, randomized, double-blind, placebo-controlled study found that once-monthly extended-release naltrexone injection was well tolerated and effective in reducing opioid use and craving and increasing treatment retention among patients with opioid dependence. The patients in the study, which was conducted at 13 sites in Russia, were predominantly male and using heroin and had a history of opioid dependence for nearly 10 years. Patients were given either placebo (n=124) or extended-release naltrexone 380 mg (n=126) injections every four weeks for 24 weeks, accompanied by biweekly sessions of manual-based individual drug counseling.

Approximately 90 percent of patients on naltrexone had opioid-free urine samples from week 5 to week 24, compared with approximately 35 percent of patients on placebo, and the difference was statistically significant. The placebo group reported no change in opioid craving on a visual analog scale throughout the 24 weeks of study, while the naltrexone group reported significant and persistent reduction in craving. The retention rate in treatment was 53.2 percent in the naltrexone group and 37.9 percent in the placebo group, which was also a statistically significant difference.

The study authors, led by Evgeny Krupitsky, M.D., of the St. Petersburg Regional Center of Addiction, cautioned that effective treatment of opioid dependence requires not only opioid antagonism but also overall health promotion and recovery.

This study was funded by Alkermes Inc., which manufactures extended-release naltrexone injection.

Chronic cocaine abuse may be associated with hypoglycemia, a retrospective observational study found. Faiz Cheema, M.D., and colleagues reviewed the medical records of 170 patients diagnosed with cocaine dependence who were admitted to the Bergen Regional Medical Center in New Jersey between January 2007 and January 2009. Twenty-two patients (12.9 percent) had hypoglycemia, defined as having a fasting blood glucose level of below 70 mg/dL; five (2.9 percent) had hyperglycemia with fasting blood glucose higher than 125; and the rest were euglycemic. The authors pointed out that clinicians should be mindful of hypoglycemia as well as hyperglycemia when treating chronic cocaine users.

Family structure in early childhood may influence suicide and suicide attempts later in life, according to a large epidemiological study from Finland. In a longitudinal cohort of 10,742 persons born in 1966 in northern Finland, 121 suicide attempts and 69 suicides were identified in 271 people (2.4 percent) from birth through the end of 2005. Because the demographic and family data were extensively recorded for this cohort, the authors, led by Antti Alaraisanen, M.D., of the University of Oulu, were able to analyze and identify family-related factors at the time of the mother's pregnancy and delivery for the offspring's risks of suicide and suicide attempts.

Having a psychiatric disorder was a significant risk factor for both male and female subjects in the offspring. The presence of a psychiatric disorder in either or both parents was associated with higher risk of suicide attempts in female offspring, and the mother's having a psychiatric disorder was associated with increased risk of suicide in male offspring.

After statistically controlling for psychiatric disorders in the parents and offspring to exclude the confounding influence of genetic risk factors, being born to a single-parent family was significantly associated with suicide attempts among male offspring, and mother's grand multiparity, or having five or more previous pregnancies, was significantly associated with suicides among male offspring.

“Suicide seems to be a long process that begins even before birth,” the authors concluded.