GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.
Roffman JL, Lamberti JS, Achtyes E, et al. JAMA Psychiatry. 2013;70(5):481-489.
Objective : More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation. This study aimed to determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response.
Results : Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P=.02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P=.03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups.
Conclusions :Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms.
Negative symptoms together with cognitive problems account for much of the disability in schizophrenia. Yet, negative symptoms remain an unmet therapeutic need. It is therefore encouraging to learn that simple, oral folate supplementation with 2 mg per day might improve negative symptoms in some patients with schizophrenia. What sets this study apart from other supplementation treatment trials in schizophrenia is the inclusion of gene information. Not surprisingly, not all patients benefited equally from folate supplementation. Instead, variation in a gene associated with folate absorption, FOLH1 was associated with improvement in negative symptoms in the intervention group. This study is thus a fine example of personalized medicine in psychiatry where treatment-response is linked to genetic variations in metabolic pathways. Future treatment trials need to figure out ways of optimally delivering folate that circumventing genetic problems with absorbing or activating folate for example. One size ("2 mg of folate orally for everybody") might not fit all.
Stahl SM, Cucchiaro J, Simonelli D, et al. J Clin Psychiatry. 2013;74(5):507-515.
Objective : The primary objective was to evaluate the safety and tolerability of lurasidone, a new atypical antipsychotic agent, in the longer-term treatment of schizophrenia (DSM-IV). Persistence of symptom improvement was assessed as a secondary outcome.
Of 254 enrolled patients, 113 (44.5%) completed 6 months of open-label treatment. During the open-label study (month 6 observed cases), small decreases were observed in mean weight (-0.1 kg) and median lipid levels (total cholesterol, -6.5 mg/dL; low-density lipoprotein, 0.0 mg/dL; high-density lipoprotein, 0.0 mg/dL; triglycerides, -8.5 mg/dL). Patients previously treated with olanzapine (n=69) experienced decrease in weight and improvement in lipid levels, whereas patients previously treated with lurasidone (n=115) or placebo (n=62) experienced minimal changes. No clinically meaningful changes were observed in median prolactin levels. The 2 most commonly reported adverse events were akathisia (13.0%) and insomnia (11.0%). Persistent antipsychotic efficacy of lurasidone was shown for patients who had previously received lurasidone, olanzapine, or placebo; further reductions from open-label baseline to final visit were observed in mean PANSS total score (-8.7) for all patients.
Open-label treatment with flexibly dosed lurasidone (40-120 mg/d) was generally safe, well tolerated, and effective over a 6-month period in patients who had completed a preceding 6-week, double-blind study.
Lurasidone is one of the more recently approved second-generation antipsychotics for the treatment of schizophrenia. It has clearly been shown to be an effective antipsychotic. However, the market is already crowded with effective antipsychotics so clinicians might rightly ask: so what? This current 6-month extension of an acute treatment study (one of the registration trials) hints at excellent long-term metabolic safety data for lurasidone. Activation (akathisia and insomnia) was the most frequent clinical problem. If this finding holds up in routine clinical care (i.e., good efficacy with a good metabolic safety profile), lurasidone deserves consideration for the maintenance treatment of patients with schizophrenia. However, it would be a mistake to assume that individual patients will not gain weight while taking lurasidone (i.e., that it is "weight neutral"). Lurasidone appears to have a relatively low propensity for weight gain and metabolic problems, particularly compared to olanzapine. It would be interesting to see how lurasidone compares to an older drug like perphenazine (the mid-potency first-generation antipsychotic from the CATIE trial that had a surprisingly good efficacy and side-effect profile) with regards to extrapyramidal symptoms including tardive dyskinesia and metabolic problems.
Daumit GL, Dickerson FB, Wang NY, et al. New Engl J Med. 2013;368(17):1594-1602.
Objective : Overweight and obesity are epidemic among persons with serious mental illness, yet weight-loss trials systematically exclude this vulnerable population. Lifestyle interventions require adaptation in this group because psychiatric symptoms and cognitive impairment are highly prevalent. Our objective was to determine the effectiveness of an 18-month tailored behavioral weight-loss intervention in adults with serious mental illness.
Results : 291 participants underwent randomization, and data on weight at 18 months were obtained from 279 participants (Table). Weight loss in the intervention group increased progressively over the 18-month study period and differed significantly from the control group at each follow-up visit. There were no significant between-group differences in adverse events.
Baseline Characteristics (N=291)
102.7 kg (225.9 lb)
18-Month Follow-Up (N=278)
Between-groups weight difference
-3.2 kg (-7 lb, P=.002)
>5% weight loss (P=.009)
Conclusion :A behavioral weight-loss intervention significantly reduced weight over a period of 18 months in overweight and obese adults with serious mental illness. Given the epidemic of obesity and weight-related disease among persons with serious mental illness, our findings support implementation of targeted behavioral weight-loss interventions in this high-risk population. (Funded by the National Institute of Mental Health; ACHIEVE ClinicalTrials.gov number, NCT00902694.).
Managing obesity is a vexing yet important clinical task for clinicians caring for patients with serious mental illness (SMI), who die much younger than their peers without mental illness. This excess mortality is in part related to obesity and its associated morbidities such as diabetes. The randomized-controlled trial by Daumit et al. showed that a behavioral weight loss intervention can be implanted in typical psychiatric outpatient settings that care for patients with SMI. Over 18 months, the intervention group in this trial lost on average 7 pounds more than the control group (which lost almost no weight). Unfortunately, the study could not show that this weight loss led to improvements in blood pressure, fasting lipids, and glucose. This study is nevertheless important as it counteracts the prevailing view that patients with SMI cannot be engaged sufficiently to participate and succeed in behavioral interventions (an example of stigma). By default, the study cohort is representative only for those patients who agree to participate in a clinical trial and who are actively engaged in psychiatric rehabilitation which is where patients were recruited. The Daumit study succeeded in setting up such a program in the psychiatric rehabilitation settings that patients were already engaged in; there was no need to reinvent the wheel in the form of creating a new treatment setting which is encouraging. The challenge for any real-world psychiatric program is to set up behavioral programs that can provide the structure and intensity needed to (A) initially engage all patients (including those with negative symptoms who might need a behavioral intervention the most); and (B) keep them engaged over time so that weight loss is sustained.
Ghanizadeh A, Nikseresht MS, Sahraian A. Schizophrenia Res. 2013;147(1):110-115.
Objective : Many patients with schizophrenia suffer from metabolic symptoms and weight gain which predispose them to obesity, diabetes, and cardiovascular problems. This trial examines the efficacy and safety of zonisamide on weight and body mass index in patients with schizophrenia being administered with atypical antipsychotics.
Results : The two groups were not statistically different regarding baseline characteristics on age, gender, education, diagnosis, weight, body mass index, daily cigarette smoking, and the duration of illness. After 10 weeks, the patients in the placebo group had significantly gained weight, while the patients in the zonisamide group lost weight (Table). The changes of body mass index in the two groups were significantly different. Body mass index decreased in the zonisamide group while it increased in the placebo group. There was a significance difference between the two groups regarding waist circumference at the end of trial (P0.0001), as well. The waist increased in the placebo group while it decreased in the zonisamide group, as well. The frequencies of adverse effects were not significantly different between the two groups and zonisamide was tolerated well.
1.9 kg (2.2)
-1.1 kg (-1.4)
Conclusion : Zonisamide as an adjuvant treatment is tolerated well and markedly affect on the weight loss of patients with schizophrenia being treated with atypical antipsychotics.
Preventing antipsychotic-induced weight gain is one critical goal of schizophrenia care. Investigating add-on medications (as opposed to life-style interventions) that can prevent antipsychotic-induced weight gain is an important endeavor for 2 reasons. For one, not all patients will have access to comprehensive and longitudinal behavioral health interventions such as the study reviewed earlier (i.e., Daumit et al. NEJM 2013). Second, not all patients will be motivated to participate in a behavioral intervention or succeed in the long run. In the current placebo-controlled trial, the antiepileptic drug zonisamide led to some weight loss in the zonisamide arm of the study but not the placebo arm. The trial was small (N=41) and short (10 weeks) but it points the way towards the next series of studies which need to be longer and compare different approaches that have been shown to prevent antipsychotic-induced weight loss (e.g, metformin, topiramate). In the not so distant future, genetic markers will hopefully help clinicians select the optimal add-on agent to prevent antipsychotic-induced weight gain.
Zivin K, Pfeiffer PN, Bohnert AS, et al. Am J Psychiatry. 2013;170(6):642-650.
Objective : A recent Food and Drug Administration (FDA) warning cautioned that citalopram dosages exceeding 40 mg/day may cause abnormal heart rhythms, including torsade de pointes. The authors assessed relationships between citalopram use and ventricular arrhythmias and mortality.
Results : Citalopram daily doses >40 mg were associated with lower risks of ventricular arrhythmia, all-cause mortality, and noncardiac mortality compared with daily doses of 1-20 mg. No increased risks of cardiac mortality were found. Citalopram daily doses of 21-40 mg were associated with lower risks of ventricular arrhythmia compared with dosages of 1-20 mg/day but did not have significantly different risks of any cause of mortality. The sertraline cohort revealed similar findings, except there were no significant associations between daily dose and either all-cause or noncardiac mortality.
Citalopram >40 mg
Citalopram 21-40 mg
AHR 0.68, 95% CI=0.61-0.76
AHR 0.80, 95% CI=0.74-0.86
AHR 0.94, 95% CI=0.90-0.99
AHR 0.90, 95% CI=0.86-0.96
AHR=adjusted hazard ratio.
Conclusions : This large study found no elevated risks of ventricular arrhythmia or all-cause, cardiac, or noncardiac mortality associated with citalopram dosages >40 mg/day. Higher dosages were associated with fewer adverse outcomes, and similar findings were observed for a comparison medication, sertraline, not subject to the FDA warning. These results raise questions regarding the continued merit of the FDA warning.
Many drugs can cause a dose-dependent prolongation of the QTc interval on the ECG. In psychiatry, the SSRI antidepressant citalopram is one such drug. It led the FDA to add a black box warning, limiting the maximum citalopram dose to 40 mg per day. While theoretically logical (higher doses will lead to increased QTc will lead to torsades will lead to death), it is unclear if this measurable yet small increase in the QTc interval actually increases deaths. The problem is that QTc is only a surrogate marker and not the actual endpoint outcome of interest (which are arrhythmias and/or death). It is therefore very reassuring that the current large epidemiological cohort study conducted in the VA system did not find citalopram >40 mg/day to be associated with adverse cardiac outcomes including cardiac death. On the other hand, clinicians cannot simply ignore the possibility of a very rare yet catastrophic outcome in a patient who starts a QTc-prolonging drug (the FDA is right in this regard). What is a clinician to do? Clinicians should view citalopram as one possible component risk factor that can contribute to dangerously high QTc but only if other component risk factors are also present. Component risk factors to look for are low magnesium or potassium levels; heart disease; other QTc-prolonging drugs; inhibitors of citalopram metabolism, or a genetically determined metabolism that would lead to increased citalopram levels. In high-risk clinical situation, one should consider obtaining a baseline ECG or choosing a different antidepressant. This discussion should remind clinicians of the ziprasidone story. Like citalopram, ziprasidone can potentially increase QTc. Like citalopram, the average increase is for almost all patients clinically irrelevant and has not been shown in epidemiological studies to lead to increased cardiac deaths (the ZODIAC study in Am J Psychiatry 2011;168:193-201).
Boyer L, Lancon C, Baumstarck K, et al. Br J Psychiatry. 2013;202:447-453.
Objective : Quality of life (QoL) measurements are increasingly considered to be an important evaluation of the treatment and care provided to patients with schizophrenia. However, there is little evidence that assessing QoL improves patient outcomes in clinical practice. The goal of this study was to investigate the impact of a QoL assessment with feedback for clinicians regarding satisfaction and other health outcomes in patients with schizophrenia.
Results : We randomly assigned 124 patients into groups. Quality of life feedback significantly affected patient satisfaction. Global satisfaction was significantly higher in the QoL feedback group compared with the other two groups (Table). Despite trends towards decreased severity for all clinical outcomes and increased changes to medication in the QoL feedback group at 6-month follow-up, these effects were not significant.
QoL Feedback Group
Standard Psychiatric Assessment
QoL Assessment Group
Conclusions : Quality of life feedback positively influences patient satisfaction, which confirms the relevance of measuring QoL in clinical practice. The absence of a significant effect of QoL feedback on clinical outcomes also suggests that clinicians did not use these data optimally. Our findings suggest a nocebo effect of QoL assessment without feedback that should be considered by researchers and clinicians.
In chronic medical conditions, quality of life is an important clinical outcome that matters to patients, and a measure of quality of life is often added to patient assessments. The current randomized study adds a caveat to this practice: patients who are asked to fill out a quality of life assessment were less satisfied with their care if their clinicians did not receive feedback about their quality of life score compared to patients whose clinicians received such feedback. This study is a good example of a real-world intervention that when done right can improved patient-physician communication. However, it is also a reminder that mandates ("let’s measure quality of care") can have unintended consequences, even if done with good intentions but with no intention to use the data.
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