GME Logo

User login

User menu

GME Research Review

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.


ISSUE 18, September 2013 — Guest Commentator: Oliver Freudenreich, MD, Harvard Medical School

Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia

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.

Method :

  • This was a parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with folic acid 2 mg and vitamin B12 400 μg.
  • Three community mental health centers affiliated with academic medical centers in the United States were utilized.
  • Participants consisted of outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, treated with an antipsychotic agent for > 6 months at a stable dose for > 6 weeks, and scored > 60 on the Positive and Negative Syndrome Scale.
  • 140 subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo.
  • Outcomes were: change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale).

: 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.

Clinical Commentary
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.


Effectiveness of Lurasidone for Patients with Schizophrenia Following 6 Weeks of Acute Treatment with Lurasidone, Olanzapine, or Placebo: a 6-Month, Open-Label, Extension Study

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.

Method :

  • This was a 6-month, open-label, extension study of flexibly dosed lurasidone 40 to 120 mg/day, conducted from March 2008 to December 2009.
  • Patients completed a prior 6-week, double-blind, placebo-controlled study evaluating the efficacy of fixed doses of once-daily lurasidone (40 or 120 mg) or olanzapine 15 mg (to confirm assay sensitivity)
  • Assessments of safety and tolerability were conducted at open-label baseline, at day 10, and monthly thereafter.

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.

Conclusions :
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.

Clinical Commentary
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.


A Behavioral Weight-Loss Intervention in Persons with Serious Mental Illness

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.

Methods :

  • Overweight or obese adults were recruited from 10 community psychiatric rehabilitation outpatient programs and randomly assigned to an intervention or a control group.
  • Participants in the intervention group received tailored group and individual weight-management sessions and group exercise sessions.
  • Weight change was assessed at 6, 12, and 18 months.

: 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)


Schizophrenia/schizoaffective disorder


Bipolar disorder


Major depression


BMI (mean)


Weight (mean)

102.7 kg (225.9 lb)

18-Month Follow-Up (N=278)

18-month follow-up

   Between-groups weight difference

-3.2 kg (-7 lb, P=.002)

   >5% weight loss (P=.009)

       Intervention group

       Control group





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 number, NCT00902694.).

Clinical Commentary
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.


The Effect of Zonisamide on Antipsychotic-Associated Weight Gain in Patients with Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

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.

Method :

  • This was a 10-week, double blind randomized placebo controlled clinical trial.
  • 41 patients with schizophrenia diagnosed according to DSM-IV-TR criteria who were taking a stable dose of atypical antipsychotic were allocated into one of the two groups of zonisamide or placebo group.
  • Weight, body mass index, waist circumference, and adverse effects were assessed.

: 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.

After 10 Weeks

Mean (SD)

Mean (SD)


1.9 kg (2.2)

-1.1 kg (-1.4)


2.2 (6.9)

-0.3 (0.4)

Waist circumference

1.1 (1.7)

-0.7 (1.2)

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.

Clinical Commentary
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.


Evaluation of the FDA Warning Against Prescribing Citalopram at Doses Exceeding 40 mg

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.

Method :

  • A cohort study was conducted using Veterans Health Administration data between 2004 and 2009
  • The study included depressed patients who received a prescription for citalopram (N=618,450) or for sertraline (N=365,898), a comparison medication with no FDA warning.
  • Cox regression models, adjusted for demographic and clinical characteristics were used to examine associations of antidepressant dosing with ventricular arrhythmia and cardiac, noncardiac, and all-cause mortality.

: 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

Ventricular arrhythmia

AHR 0.68, 95% CI=0.61-0.76

AHR 0.80, 95% CI=0.74-0.86

All-cause mortality

AHR 0.94, 95% CI=0.90-0.99


Noncardiac mortality

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.

Clinical Commentary
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).


Evaluating the Impact of a Quality of Life Assessment with Feedback to Clinicians in Patients with Schizophrenia: Randomised Controlled Trial

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.

Method :

  • We conducted a 6-month, prospective, randomised, and controlled open-label study.
  • Patients with schizophrenia were assigned to one of three groups: standard psychiatric assessment; QoL assessment with standard psychiatric assessment; and QoL feedback with standard psychiatric assessment.
  • The primary outcome was patient satisfaction at 6 months.
  • The local ethics committee (Comité de Protection des Personnes Sud-Méditerranéee V, France, trial number 07 067) and the French drug and device regulation agency (Agence Française de Sécurité Sanitaire des Produits de Santé, France, trial number A01033-50) approved this study.

: 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.

Groups (N=124)

Global Satisfaction:
High Level

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.

Clinical Commentary
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.

GME Research Review

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.


ISSUE 17, August 2013 — Guest Commentator: Terence E. Ketter, MD, Stanford School of Medicine Stanford, CA


Lithium in the Prevention of Suicide in Mood Disorders: Updated Systematic Review and Meta-Analysis

Cipriani A, Hawton K, Stockton S, Geddes JR.
Br Med J. 2013 (ePub).

Objective: To assess whether lithium has a specific preventive effect for suicide and self-harm in people with unipolar and bipolar mood disorders.


  • Systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo or active drugs in long-term treatment of mood disorders.
  • Studies up to January 2013 were utilized.
  • The main outcomes were the number of people who completed suicide, engaged in deliberate self-harm, and died from any cause.

48 randomized controlled trials including 6,674 participants were included in the analysis. Lithium was more effective than placebo in reducing number of suicides and deaths from any cause, but not in preventing deliberate self-harm. In unipolar depression, lithium compared to placebo was associated with a reduced risk of suicide and number of total deaths.

Conclusions: Lithium was effective for reducing risk of suicide in people with mood disorders. Lithium’s antisuicidal effects appear at least in part mediated by reducing mood disorder relapse. However, additional mechanisms, such as reducing aggression and impulsivity, need to be considered.

Clinical Commentary
Psychiatric disorders in general, and mood disorders in particular, are associated with increased suicide risk. Aside from the notable exception of clozapine in schizophrenia, the role of psychotropics in suicide prevention remains to be established. This updated review extends data suggesting lithium’s efficacy in reducing the risk of suicide in people with mood disorders, including unipolar major depressive disorder. These data thus extend support for lithium’s role in the treatment of mood disorders to include a possible specific utility in people at risk for suicide. As such, combining lithium with psychosocial, educational, and means-reduction strategies could enhance efforts to prevent suicide in people with mood disorders.


Lithium Moderate-Dose Use for Bipolar Disorder (LiTMUS): A Randomized Comparative Effectiveness Trial of Optimized Personalized Treatment with and without Tolerable Doses of Lithium

Nierenberg AA, Friedman ES, Bowden CL, et al
Am J Psychiatry. 2013;170(1):102-110.

The authors investigated the comparative effectiveness of tolerable dosages of lithium as part of optimized personalized treatment (OPT).


  • 283 bipolar disorder outpatients were randomized to 6 months of single-blind (rater), flexible, moderate dosages (most often 600 mg/day) of lithium plus OPT or 6 months of OPT alone.
  • The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder–Overall Severity (CGI-BP-OS) and “necessary clinical adjustments” (medication adjustments per month).
  • Sustained remission (CGI-BP-OS score ≤2 for 2 months) and treatment with second-generation antipsychotics were also assessed.
  • The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.

Longer-term (6 months) treatment with lithium plus OPT was most often adequately tolerated, with only 21% of patients discontinuing lithium. However, the authors observed no statistically significant advantage of lithium (mean final serum concentration 0.47 mEq/L) plus OPT on CGI-BP-OS scores, necessary clinical adjustments, or proportion with sustained remission. However, fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively).

Conclusions: In this pragmatic comparative effectiveness study, a moderate but tolerated dosage of lithium plus OPT conferred no symptomatic advantage when compared with OPT alone, but the lithium-plus-OPT group had less exposure to second-generation antipsychotics. Only about one-quarter of patients in both groups achieved sustained remission of symptoms. These findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.

Clinical Commentary
This study addresses an important issue in the contemporary management of bipolar disorder – namely, the potential role of moderately-dosed lithium in combination with OPT. It is clear from this work that moderately-dosed lithium in combination with OPT had adequate tolerability. However, determining clinical effectiveness (i.e. integrating the efficacy and tolerability implications) of this approach is more complex. Specifically, although use of moderately-dosed lithium combined with OPT failed to yield significant improvements in efficacy outcomes, it did permit approximately 14% less use of second-generation antipsychotics. Thus, moderately-dosed lithium combined with OPT could prove to be a strategy worth exploring for bipolar disorder patients for whom avoiding second-generation antipsychotics is a priority.



Lurasidone Monotherapy for the Treatment of Bipolar I Depression: Results of a 6-Week, Double-Blind, Placebo-Controlled Study

Loebel A, Cucchiaro J, Silva R, et al
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Poster Session II. Bipolar Disorders, 15:138. doi: 10.1111/bdi.12084


Objective: To evaluate the efficacy and safety of lurasidone, flexibly dosed at 20­-60 mg/d or 80-120 mg/d, in the treatment of major depressive episodes in patients with bipolar I disorder without psychotic features.

Methods: 505 subjects with DSM-IV-TR bipolar I depression, with or without rapid cycling, with baseline MADRS score ≥20 were randomized to 6 weeks of once-daily, double-blind treatment with either lurasidone 20-60 mg/d, lurasidone 80-120 mg/d, or placebo.

Results: Lurasidone treatment resulted in significantly greater reduction in MADRS scores at Week 6 endpoint for both lurasidone 20-60 mg/d and lurasidone 80-120 mg/d versus placebo. Both lurasidone groups separated significantly from placebo from week 2 onward. Minimal changes in weight, lipids and measures of glycemic control were observed.


Lurasidone 20-60 mg/day

Lurasidone 80-120 mg/day


Responder rates*




Discontinuation rates due to adverse events
















*MADRS reduction ≥50%.

Conclusions: In this study, monotherapy with lurasidone, flexibly dosed at 20-60 mg/d or 80-120 mg/d, significantly reduced depressive symptoms in patients with bipolar I depression compared to placebo. Tolerability and safety of lurasidone was consistent with results of previous studies in schizophrenia.

Clinical Commentary
These data, along with those of a companion lurasidone adjunctive therapy (added to lithium or valproate) bipolar I depression study (Bipolar Disorders 2013;15(Suppl 1):137-8) were the basis for the recent United States Food and Drug Administration (US FDA) approval of lurasidone monotherapy and adjunctive therapy (added to lithium or valproate) for the treatment of bipolar I depression. This has great clinical significance, as it constitutes the first approval of a new medication for bipolar depression since 2006. Depression is the predominant abnormal mood state in bipolar disorder, and there were previously only two US FDA-approved treatments (olanzapine and fluoxetine combination and quetiapine monotherapy), both of which were similarly likely to yield harm (weight gain and sedation) and benefit (response). The approval of a treatment that is more than twice as likely to yield benefit (response) as harm (akathisia or nausea) provides an important new option for patients with bipolar I depression.



A Double-Blind, Placebo-Controlled, Multicenter Trial of Adjunctive Armodafinil for the Treatment of Major Depression Associated with Bipolar I Disorder

Ketter TA, Calabrese JR, Yang R, Frye MA.
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Poster Session I. Bipolar Disorders, 15:88. doi: 10.1111/bdi.1208


Objective: The objective of this study was to evaluate the efficacy and safety of armodafinil as an adjunctive therapy for major depression associated with bipolar I disorder.


  • Participants consisted of patients 18–65 years of age with bipolar I disorder currently experiencing a major depressive episode while taking 1 or 2 of the following medications: lithium, valproate, olanzapine, aripiprazole, risperidone, lamotrigine, or ziprasidone (only in combination with lithium or valproate).
  • Patients were randomized to armodafinil 150 mg/d, 200 mg/d, or placebo.
  • The primary outcome was the mean change from baseline to week 8 in the 30-item Inventory of Depressive Symptomatology–Clinician-rated (IDS-C30) total score.

433 patients were randomized to placebo, armodafinil 150 mg, or armodafinil 200 mg. Randomization to the 200 mg armodafinil group was discontinued early; data from this group were included in safety analyses only. There was a significantly greater IDS-C30 total score decrease at week 8 for the armodafinil 150 mg/d group compared with placebo.


Placebo (n=199)

Armodafinil 150 mg (n=201)

Armodafinil 200 mg (n=33)

IDS-C30 responders: Week 8

IDS-C30 responders: final visit






Weight gain ≥7%




Discontinuation due to adverse events
















Conclusions: Adjunctive armodafinil 150 mg/d significantly improved depressive symptoms compared with placebo in patients with a major depressive episode associated with bipolar I disorder. Safety data indicated that adjunctive armodafinil 150 mg/d was generally well tolerated.

Clinical Commentary
These data, like those from the above-mentioned lurasidone study, address an important unmet need in the management of bipolar I depression – the need for not only effective, but also well-tolerated, treatments. It is clear that armodafinil has tolerability that is superior to the first two treatments approved for bipolar depression (olanzapine and fluoxetine combination and quetiapine monotherapy). However, the clinical significance of this study depends on this finding being replicated, which is necessary for US FDA approval for bipolar I depression, and for armodafinil to become a substantive new option for patients with bipolar I depression.



Cariprazine Effects on YMRS Items: Results of a Pooled Analysis of 3 Randomized, Double-Blind, Placebo-Controlled Trials in Bipolar Mania

Keck PE, Zukin S, Lu K, Laszlovszky I, Durgam S.
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Poster Session I. Bipolar Disorders, 15:87. doi: 10.1111/bdi.1208

Objective: The second-generation antipsychotic cariprazine is a potent dopamine D3/ D2 receptor partial agonist with preferential binding to dopamine D3 receptors that has demonstrated efficacy in 3 randomized, double-blind, placebo-controlled trials in acute bipolar mania. This pooled analysis evaluated the effects of cariprazine on Young Mania Rating Scale (YMRS) single items to investigate efficacy across mania symptom domains.


  • Data were pooled from 3 cariprazine studies in patients with acute mania or mixed episodes associated with bipolar I disorder.
  • Cariprazine was flexibly dosed (3-12 mg/day) in 2 studies; the third study used a fixed/flexible dose design (3-6 mg/day, 6-12 mg/day).
  • Post hoc pooled analysis evaluated change from baseline to Week 3 in individual items of the YMRS using a mixed-effects model for repeated measures.

A total of 1,037 patients (cariprazine, n=608; placebo, n=429) who received at least 1 dose of study medication and had at least 1 post-baseline YMRS assessment were included in the analysis. In each of the three individual trials, cariprazine showed significant advantage versus placebo on YMRS total score improvement. Moreover, in the pooled analysis, cariprazine was significantly superior to placebo for improvement on all 11 individual YMRS items (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech, language, content, disruptive-aggressive behavior, appearance, and insight).

Conclusions: Cariprazine demonstrated efficacy on all 11 individual YMRS items (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech, language, content, disruptive-aggressive behavior, appearance, and insight) in this pooled analysis. These results suggest that cariprazine has broad efficacy across symptoms in the treatment of acute mania associated with bipolar I disorder.

Clinical Commentary
These data extend the findings of three studies indicating cariprazine efficacy in acute mania, to indicate a broad spectrum of efficacy with respect to diverse individual symptoms of mania. The demonstrated utility of cariprazine in acute mania has led to the US FDA considering approval of cariprazine for acute mania. Should the US FDA approve cariprazine for this indication, this would have clinical impact in that cariprazine would be a new option for patients with bipolar I disorder with a current manic episode.



Antidepressant Use in Bipolar Disorder: International Society for Bipolar Disorder Task-Force Consensus Report

Vieta E, for the International Society for Bipolar Disorders Task-Force on Antidepressants in Bipolar Disorder.
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Symposiums. Bipolar Disorders, 15:12-13. doi: 10.1111/bdi.12079


Objective: The International Society for Bipolar Disorders Task-Force sought to develop consensus recommendations on the use of antidepressants in bipolar disorder.

Methods: The expert Task-Force iteratively developed consensus, using the Delphi method. Initial survey items were based on systematic review of the literature, and subsequent iterative surveys were performed to yield final recommendations.

Results: Evidence of efficacy and safety of antidepressants in bipolar disorder is limited and inconsistent. Well-designed, long-term trials of prophylactic benefits are scant. There is insufficient evidence for treatment benefits with antidepressants combined with mood-stabilizers. There is striking disparity between the very common clinical use of antidepressants in bipolar disorder, and the weak evidence-base to support such use. Risks for mood switches to hypomania, mania, and mixed-states are important concerns. Consensus was achieved for 12 statements regarding the use of antidepressants in bipolar disorder.

Conclusions: Due to data limitations, broad statements were not possible endorsing antidepressants in bipolar disorder. However, selective serotonin reuptake inhibitors (SSRIs) and bupropion may have lower manic switch rates than tricyclic antidepressants (TCAs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) in adults. The frequency and severity of antidepressant-associated mood elevations appear greater in bipolar I disorder than bipolar II disorder patients. Thus, in bipolar I disorder patients antidepressants should only be used as adjuncts to antimanic medications.

Clinical Commentary
These data confirm a persistent unmet need in bipolar disorder research – namely, the need for definitive studies regarding the role of antidepressants in bipolar disorder. Thus, although antidepressants are very commonly used in patients with bipolar depression (perhaps due to their generally adequate somatic tolerability), evidence of their efficacy and safety (i.e. risk of mood elevation) is limited and inconsistent.


GME Research Review

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.


ISSUE 16, JULY 2013 — Guest Commentator: Peter Selby, MBBS, CCFP, University of Toronto, Canada


Pharmacological Interventions for Smoking Cessation: An Overview and Network Meta-Analysis

Cahill K, Steven S, Perera R, Lancaster T.
Cochrane Database Syst Rev. 2013 May 31;5:CD009329.

Objectives: There were 4 objectives of this overview and comparative effectiveness of various firs- line pharmacotherapies for smoking cessation.

  • Is nicotine replacement therapy (NRT) bupropion and varenicline better than placebo and are there differences between these medications in helping smokers achieve long-term abstinence (6 months or longer)?
  • How do other treatments, such as clonidine and nortriptyline, compare with placebo in achieving long-term abstinence?
  • Are some options safer than others?
  • When do the risks of harm outweigh the benefits of smoking cessation medications?


  • This overview was restricted to Cochrane reviews, all of which include randomized trials.
  • Inclusion: These studies were restricted to adult smokers. Medications included in the review included NRT, antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate.
  • Exclusions: Studies exclusively done on pregnant women, particular disease groups, or specific settings.
  • Outcome measures: for benefit -continuous or prolonged abstinence at least 6 months from the start of treatment compared to placebo or each other.
  • For harms – the incidence of serious adverse events.
  • Search strategy: Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with “smoking” in the title, abstract, or keyword fields. The last search was conducted in November 2012.
  • Methodological quality was assessed using a revised version of the AMSTAR scale, which is a validated tool to rate the quality of systematic reviews.
  • The authors conducted a network meta-analyses to compare between active treatment and to compare the risks of serious adverse events between varenicline and bupropion. This is a method utilized when multiple interventions have been used and compared for the same disease and outcomes, and allows for the interpretation of the overall evidence and to understand the relative merits of these multiple interventions.


  • Twelve treatment-specific reviews were identified, including a total of 267 studies, representing 101,804 smokers most of whom smoked 10 or more cigarettes per day.
  • For every 10 smokers who quit with placebo, 18 quit with NRT or bupropion (odds ratios [OR] 1.84; 95% credible interval [CredI] 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively).
  • Bupropion and NRT were equally efficacious (OR 0.99; 95% CredI 0.86 to 1.13).
  • For every 10 smokers who quit with placebo, 28 quit with varenicline (OR 2.88; 95% CredI 2.40 to 3.47).
  • Varenicline was more efficacious than monotherapy NRT (OR 1.57; 95% CredI 1.29 to 1.91), and bupropion (OR 1.59; 95% CredI 1.29 to 1.96).
  • Varenicline was superior to the nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and “other” NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT was better than single formulations.
  • The four categories of NRT performed similarly against each other, apart from “other” NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46).
  • For every 10 quitters with placebo, 39 quit with cytisine, a nicotine receptor partial agonist, (risk ratio [RR] 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs. Cytisine is not available in North America.
  • Across the 82 included and excluded bupropion trials, the risk of seizures was lower than that expected, at about 1:1500.
  • There were no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59) in the studies of bupropion.
  • In the 14 varenicline trials, there were no differences in adverse events between varenicline and placebo (RR 1.06; 95% CI 0.72 to 1.55).  Subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56).
  • Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78).
  • Adding nortriptyline or bupropion to NRT did not improve outcomes.
  • Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18). However, the side effects negated any positive outcomes.
  • The results for other treatments were either inconclusive or failed to show any advantage over placebo.
  • Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention.


  • NRT, bupropion, varenicline, nortriptyline, and cytisine improve the chances of quitting over placebo.
  • Combination NRT and varenicline are equally effective.
  • All treatments are generally safe, but further monitoring of varenicline is required.
  • No further study is required to establish the safety and efficacy of NRT.

Clinical Commentary
Tobacco use kills almost half a million Americans annually, making it the most deadly addictive disorder. However, it is very treatable as demonstrated in the review of reviews. For every two smokers a psychiatrist helps quit, one life will be saved from premature mortality. Medications roughly double the chances of success for every quit attempt. Of note, the findings are so robust for nicotine replacement therapy (NRT), additional studies to establish efficacy are not needed. What is needed is for clinicians to use these evidence-based therapies, and this review confirms the evidence that prescribers have safe and effective options for all patients. Tobacco use disorders are highly prevalent in patients with other addictions and mental illness. Although relapse is common, repeated or even extended treatment may be necessary. In patients with psychiatric comorbidity, the choice of medication might pose a concern. However, at least two medications have indications for other psychiatric conditions, namely bupropion and nortriptyline, that are also effective options in patients who smoke. Varenicline might be associated with idiosyncratic neuropsychiatric side effects so education and monitoring is required for emergent depression and suicidal or homicidal ideation. From a safety perspective, NRT does not provide the 4000-7000 chemicals present in smoke that are associated with harm. Combination NRT maybe more effective because a greater percent of baseline nicotine is replaced. The reviews included in this study also establish that concurrent smoking with NRT is safe and more effective than quitting abruptly. Although not specifically included in this review, there is evidence of safety for the use of varenicline in patients with stable schizophrenia. This review also did not address the role of nicotine to manage acute nicotine withdrawal in psychiatric patients admitted to hospitals where they are not allowed to smoke. In conclusion, psychiatrists can be reassured that they can treat patients who smoke with a combination of pharmacotherapy and counseling to reduce the premature mortality that frequently befalls these patients.


A Randomized, Double-Blind, Placebo-Controlled Trial of Venlafaxine Extended Release for Co-occurring Cannabis Dependence and Depressive Disorders

Levin FR, Mariani J, Brooks DJ, et al
Addiction. 2013;108(6):1084-1094.

 Is venlafaxine-extended release (VEN-XR) an effective treatment for cannabis dependence with concurrent depressive disorders?


  • 12-week randomized, double-blind, placebo-controlled trial of outpatients (n=103).
  • Adults between the ages of 18-60 years with DSM-IV-TR cannabis dependence with marijuana as their primary drug of abuse, and major depressive disorder or dysthymia.  
  • Hamilton Depression Rating Scale (HDRS) score at least 12 with depression for at least 3 months.
  • Excluded were individuals with psychotic disorders, bipolar disorders, and those who failed to respond to venlafaxine in the past or were allergic to it. Women who were pregnant or lactating were excluded as well.
  • Patients received up to 375 mg venlafaxine extended release (XR) on a fixed-flexible schedule or placebo and weekly individual cognitive-behavioral psychotherapy that primarily targeted marijuana use.
  • The trial included a 1-week placebo lead-in phase, a 3-week medication titration phase, and an 8-week medication maintenance phase.
  • Placebo responders were not randomized and excluded from the analyses.

The primary outcome measures were: (1) abstinence from marijuana defined as at least two consecutive urine-confirmed abstinent weeks and; (2) improvement in depressive symptoms based on the HRDS. Missing data was interpreted as being positive for use of marijuana.


  • 63% of venlafaxine- and 69% of placebo-treated patients had clinically significant mood improvement (50% decrease in HDRS score from baseline) (χ12 = 0.48, P=0.49).
  • Abstinence rates were significantly worse on VEN-XR (11.8%) compared to placebo (36.5%) (χ12 = 7.46, P<.01; odds ratio=4.51, 95% confidence interval: 1.53, 13.3).
  • For every 10 ng/ml increase in the THC urine level at baseline, there was a 1.5% decrease in the odds of abstinence (inter-rater reliability [IRR]=0.985, 95% CI: 0.974, 0.996).
  • Mood improvement was associated with reduction in marijuana use in the placebo group (F1,179 = 30.49, P<.01), but not the VEN-XR group (F1,186=0.02, P=.89).

Conclusions: Contrary to what the authors expected, for depressed, cannabis-dependent patients, venlafaxine XR does not appear to be effective at reducing depression and may lead to an increase in cannabis use. Also heavily dependent users had a worse prognosis in this study.

Clinical Commentary
Cannabis is the most widely used illicit substance worldwide, with significant consequences including an increased risk of psychosis in vulnerable individuals. Cannabis dependence doubles the odds of a depressive disorder in the general population and depression is very common in cannabis dependence treatment-seeking patients. The investigators chose to study venlafaxine because of its dual action on serotonin and noradrenergic systems. This was justified on the basis of previous RCTs where tricyclic antidepressants appeared to be  superior to selective serotonin reuptake inhibitors in reducing substance use in depressed patients. The patients recruited were a mix of clinical treatment seekers and those recruited via advertisement. They used the SCID to define the population and excluded those whose mood  symptoms could be attributed to cannabis withdrawal. Of the subjects, 62% completed all 12 weeks of the trial. This negative trial demonstrates a significant difference between placebo and venlafaxine in this population and it could be argued that the medication increases cannabis use. The lack of effect of the active medication could be due to the ceiling effect of response produced by cognitive-behavioral therapy (CBT). Most subjects had mild to moderate depression, which is very responsive to CBT without any additional benefit from medication. The increase in use of cannabis could be explained by the adrenergic effects of venlafaxine worsening cannabis withdrawal. However, this is speculative at best. For every one patient who would achieve abstinence with CBT and placebo, four would be harmed by the addition of venlafaxine XR. In conclusion, in depressed outpatients using cannabis, it might be prudent to engage the patient in CBT to stop or reduce marijuana use before initiating treatment for depression, and venlafaxine is best avoided. However, practical considerations such as patients perceptions of the antidepressant and anxiolytic effects of marijuana will require psychoeducation and motivational interviewing to engage in CBT.


Anxiety Disorders and Drug Dependence: Evidence on Sequence and Specificity Among Adults

Goodwin RD, Stein DJ.
Psychiatry Clin Neurosci. 2013;67(3):167-173.


  • To describe the association between specific anxiety disorders and substance dependence.
  • Control for demographic confounders, such as age and sex, and comorbidities such as alcohol dependence and depression.


  • Secondary data analysis of an old cross sectional survey (1990-1992; use of DSM-III-R diagnostic criteria) but still valid for the purposes of the stated objectives of this study.
  • The database analyzed was the National Comorbidity Survey (NCS), a nationally representative population sample of the US adult population 15-54 years of age.
  • There was an 82.4% response rate.
  • The following DSM-III-R diagnoses were included: major depression, generalized anxiety disorder (GAD), simple phobia, social phobia, panic attacks, panic disorder, post-traumatic stress disorder (PTSD), alcohol dependence, and substance (illicit drug) dependence.
  • The temporal sequence of onset of anxiety and substance dependence disorders was examined.
  • Logistic regression was used to measure the association between anxiety disorders and substance dependence (past year and lifetime) while controlling for other variables.


  • All anxiety disorders were associated with substance dependence even after controlling for alcohol dependence and depression.
  • The onset of substance dependence occurred prior to the onset of anxiety disorder in a majority of cases especially in those with panic attacks, agoraphobia, GAD, and PTSD
  • The anxiety disorder preceded substance dependence in more than 50% of social phobia cases, nearly 40% of PTSD cases, and in nearly 30% of GAD cases.
  • After adjusting for depression and demographic variables, only the link between a history of agoraphobia and substance dependence remained statistically significant.
  • A lifetime history (excluding a current history) of drug dependence was associated with a significantly increased likelihood of current panic attacks, agoraphobia, panic disorder, and social phobia even after adjusting for alcohol dependence and depression. The highest association was with panic disorder (OR 2.62; 95% CI 1.29 to 5.32)

Conclusions: The strongest association was between panic disorder and past substance dependence. The authors suggest this might be due to the effects of substances on the neurocircuitry involved in panic, such as the extended amygdala. Moreover, there was an association between anxiety disorders and substance dependence not accounted for by depression or alcohol dependence. The limitations include the cross sectional nature of the study; thus, no inferences can be drawn on causality. The specificity as to which substance caused the problem was not possible due to limited sample sizes in the cells.

Clinical Commentary
In this study, substance dependence predated the onset of anxiety disorders, suggesting that self-medication might not always be the reason patients use drugs. This study points to the possibility of a substance-induced anxiety disorder or some shared vulnerability to both. Substance use is a stigmatized behavior and may be underreported in traditional psychiatric and primary care settings whilst treating anxiety disorders. Anxiety disorders are common reasons to seek care, and the use of benzodiazepines to manage these symptoms in the short term might cause vulnerable individuals to develop or worsen substance dependence. Regardless, clinicians need to be able to prevent harm and yet offer treatment to those who present with impairing levels of anxiety. Therefore, it is imperative to screen for lifetime and current substance use prior to the initiation of benzodiazepines. Moreover, stimulant use disorders and marijuana use might also be the cause of anxiety and these substance-induced anxiety disorders need to be ruled out or treated with appropriate addiction counseling before the initiation of benzodiazepines. Screening tests can include obtaining a detailed history with third-party corroboration where feasible, and a urine toxicology screen. Moreover, newer screening tools such as the Global Assessment of Individual Need-Short Screener (GAIN-SS) are highly valid and reliable whilst being easy to administer in busy ambulatory settings. There is little evidence published on the management of co-occurring anxiety disorders in patients with substance use disorders. Therefore, to balance the need for symptom control and to prevent or worsen the course of a substance use disorder, it is important to use non-addictive alternatives such as SSRIs combined with CBT to treat the anxiety disorder. Concurrent treatment of the addiction is also warranted. If benzodiazepines are prescribed, those with lower abuse liability such as clonazepam should be used. Short duration of prescriptions with pill counts and monitoring of urine toxicology might optimize management and reduce the risk of iatrogenic addiction. A pragmatic goal of treatment in patients with concurrent addiction and anxiety disorders might be improvement in quality of life and fulfillment of role responsibilities rather than complete abstinence from benzodiazepines. Further research is required to determine the optimal management of these patients.


Randomized Trial of Long-Acting Sustained-Release Naltrexone Implant vs Oral Naltrexone or Placebo for Preventing Relapse to Opioid Dependence

Krupitsky E, Zvartau E, Blokhina E, et al
Arch Gen Psychiatry. 2012;69(9):973-981.



  • To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and non-medication treatment for opioid dependence.
  • Six-month, double-blind, double-dummy, randomized trial in St. Petersburg, Russia.
  • Three hundred and six recently detoxified opioid-dependent patients between the ages  of 18 to 40 years who met DSM-IV criteria for opioid dependence.
  • Subjects had to be opioid dependent with physiological features for at least 1 year, diagnosed clinically and using the Composite International Diagnostic Interview (CIDI). 
  • To be included in the study subjects were confirmed to: be abstinent from heroin and other substances for the past week or more; have negative results of urine toxicology and alcohol breath tests; not be taking any psychotropic medication; and be able to provide informed consent.
  • They also needed to have stable housing and a family member willing to supervise therapy at home. Subjects with psychotic illness and bipolar disorder were excluded.
  • All enrolled subjects received biweekly counseling and were randomized to one of the following 3 treatments for 24 weeks after a naloxone challenge test to ensure adequate detoxification:

    (1) Naltrexone implant 1000 mg and oral placebo (NI+OP group; 102 patients)

    (2) Placebo implant and 50-mg oral naltrexone HCL  (PI+ON group; 102  patients)

    (3) Placebo implant and oral placebo (PI+OP group; 102 patients).

  • The primary outcome measure was the percentage of patients retained in treatment without relapse confirmed by urine toxicology.
  • The implants were aseptically inserted subcutaneously by a surgeon using a syringe and a small incision requiring one or two sutures and replaced every 60 to 90 days during the trial.


  • Most subjects were male and were about 28 years of age.
  • They had an average of 8 years of opioid dependence and between 3 to 6 previous treatment attempts. 
  • 47% were HIV positive ; 95% were HCV positive,
  • 26% were using marijuana and 11% were using amphetamines at baseline.  
  • NI+OP group (52.9%) remained in treatment without relapse compared with PI+ON group (15.7%) (survival analysis, log-rank test, P<.001) and PI+OP group (10.8%) (P<.001).
  • The PI+ON vs PI+OP comparison showed a non-significant trend favoring the PI+ON group (P=.07).
  • Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P<.001, Fisher’s exact test, compared with the NI+OP group).
  • Wound infection rate was 4.9% in the NI+OP group, 1.1% in the PI+ON group, 0.7% in the PI+OP group (P=.02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy.
  • Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P=.12), and all resolved with anti-allergy medication treatment. There was no increase in overdose deaths once naltrexone was discontinued.

In regions where there is no access to opioid agonist therapy, injectable naltrexone was found to be superior to oral naltrexone in retaining patients in treatment for up to 6 months. About half the patients responded to treatment and half of these relapsed after treatment ends, indicating the need for chronic treatment.

Clinical Commentary
The standard of care for opioid dependence in North America is agonist therapy with methadone or buprenorphine. However, there are patients for whom these medications are not an option either due to personal choice or availability of treatment. Injectable naltrexone, which is available in the US, might be an alternative for these patients and negates the need for daily observed ingestion of the oral formulation. Although the oral formulation performed better than placebo, these subjects had engaged family members who supervised their medication compliance. There were no reports of depression, anxiety, or anhedonia, suggesting the implant was well tolerated. The limitations of the implant are the invasive nature of the procedure and failure in 13% of subjects. Cravings were also reduced in those who remained abstinent. Given the high prevalence of HIV in this population, any treatment that can reduce injection potentially reduces the spread of the disease to others. Therefore, this option deserves serious consideration for the appropriate opioid-dependent patient who does not or cannot tolerate an opioid agonist. Weighing the risks and benefits, including the lack of efficacy of opioid agonists for acute pain should the patient require pain management, will help the patient and provider decide if this approach is a viable option. It should be noted that the implant is not available in the US but a sustained-release injectable formulation is available and is administered every 30 days. Moreover, naltrexone injection is also approved for alcohol dependence and might be well suited for those with dual opioid and alcohol dependence. In summary, naltrexone can be effective if the problem of non-adherence can be overcome by injecting or implanting a sustained-release formulation of the medication.



Predictors of the 2‐Year Recurrence and Persistence of Alcohol Dependence 

Boschloo L, Vogelzangs N, van den Brink W, et al
Addiction. 2012;107(9):1639-1640.


To identify independent risk factors of the recurrence of alcohol dependence (AD) in people with a remitted disorder at baseline and persistence of AD in people with a current disorder at baseline.


  • Secondary analysis of data from a prospective cohort study with assessments at baseline and 2-year follow-up.
  • Data were derived from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing cohort study examining the long-term course and consequences of depressive and anxiety disorders in adults (18-65 years).
  • Patients with bipolar disorder and psychosis were excluded. 
  • All participants were seen in person and assessed using the Composite International Diagnostic Interview (CIDI) to arrive at DSM-IV diagnoses.
  • Over 80% returned for a follow-up and were re -interviewed at 2 years.
  • Subjects were recruited from primary care, specialty care, and the community, representing a mix of treatment and non-treatment seeking individuals.
  • The sample consisted of 253 patients with remitted AD (n=253) and 135 patients with current AD.
  • Recurrence and persistence of AD during 2-year follow-up were established using the CIDI interview based on DSM-IV.
  • The authors described the recurrence of AD in people with remitted AD at baseline (i.e. not meeting any AD criteria in the year before baseline; median time since remission: 4 years) based on the presence of a CIDI diagnosis of AD at any time during the 2-year follow-up. 
  • Persistence of AD in people with current (i.e. past-year) AD at baseline was defined as the presence of a past-year CIDI-diagnosis of AD at the 2-year follow-up.
  • Both outcomes indicate the naturalistic course of AD, as only 4.8% of people with life-time AD participated in alcohol treatment (i.e. at an addiction treatment center or Alcoholics Anonymous) in the 6 months before baseline.
  • Logistic regression analyses were performed to explore the role of potential risk factors (i.e. baseline severity of alcohol problems, measures for depression and anxiety, socio-demographics, vulnerability factors, and addiction-related factors) as independent predictors of a negative course.


  • Overall recurrence and persistence rates of AD were 14.6 and 40.7%, respectively, and were highly conditional on the severity of alcohol problems (adjusted odds ratio [OR] per standard deviation [SD] increase: OR=3.64, 95% confidence interval [CI]: 2.21-6.01 and OR=2.12, 95% CI: 1.32-3.40, respectively).
  • Regardless of setting from where these subjects were recruited, there was a dose-response relationship between the severity of alcohol problems and recurrence. Less than 5% of the subjects had attended formal or informal addiction treatment.
  • Severity of depressive/anxiety symptoms but not disorders was an additional independent predictor of the recurrence of AD (recurrence rate: 17.4% versus 7.2%; OR=2.69, 95% CI: 1.00-7.23), whereas male gender and high education were significant independent risk factors of the persistence of AD.

Conclusions: Both recurrence and persistence of alcohol dependence are highly dependent on severity of baseline alcohol problems, whereas severity of depressive/anxiety symptoms predicts only the recurrence of alcohol dependence. Both measures may be useful in identifying people at an increased risk of a negative course and who could be targeted by prevention strategies. 

Clinical Commentary
Only 2 to 6% of treated patients with alcohol dependence remit annually. The strength of this cohort study is that participants were heterogeneous and selected from community settings, primary care settings, and mental health settings with follow-up rates of  >80%. The findings suggest that therapeutic nihilism is not warranted because the majority of subjects remit within 2 years and it is not always a chronic and relapsing disorder. The severity of alcohol problems and depressive/anxiety symptoms may be useful in identifying people at an increased risk of developing a new episode of AD. Assessment instruments such as the AUDIT , IDS, and BAI may be used to screen for alcohol problems, depressive symptoms, or anxiety symptoms, respectively. Given that the recurrence rate was only 2% in the quintile of people with the mildest alcohol problems versus 43% in the quintile of people with the most severe alcohol problems, these findings might be useful to personalize advice regarding additional treatment. The observation might be explained by either a shared diathesis for both depression/anxiety symptoms and alcohol dependence or “self-medication,” where the person is trying to mitigate negative mood states by drinking alcohol. Alcohol use disorders present a particular challenge for psychiatrists. Although alcohol use is associated with all psychiatric disorders, the causal link between the two is less well established. Often the clinician is not sure if the patient is self-medicating symptoms of anxiety or depression or if the depression or anxiety is due to alcohol intake. Although the temporal association between use and affective symptoms might provide a clue, the ideal intervention would be to examine the effects of alcohol withdrawal treatment on affective symptoms and treat residual symptoms of depression or anxiety with SSRIs and CBT.  Most alcohol-induced mood disorders improve dramatically within 1-2 weeks of abstinence. In addition, it is important to assess the immediacy of risk to the patient since most completed suicides occur during intoxication. Such patients need admission, detoxification, relapse-prevention medication such as naltrexone or acamprosate, the appropriate SSRI, and CBT and addiction counseling. Ideally, this should be provided concurrently wherever possible or at least collaboratively by mental health and addiction treatment providers. Therapy should initially focus on maintaining sobriety and resolving the effects of past trauma where appropriate, and management of depression and or anxiety with medications with low abuse potential. Monitoring the effects of SSRIs on drinking is also warranted given that some studies have found increased rates of drinking. Long-term benzodiazepine prescriptions should be avoided given the greater risk of dependence in patients with AD. 

GME Research Review

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.

ISSUE 14, May 2013 — Guest Commentator: Dan V. Iosifescu, MD, MSc, Mount Sinai School of Medicine, New York, NY


Efficacy and Mood Conversion Rate During Long-term Fluoxetine v. Lithium Monotherapy in Rapid- and Non-rapid-cycling Bipolar II Disorder

Amsterdam JD, Luo L, Shults J.
Br J Psychiatry. 2013;202:301-316.

Objectives: Multiple studies suggest an association between rapid cycling and antidepressant use in bipolar disorder.  To test the hypothesis that antidepressant monotherapy is associated with poor outcomes, this study reports an exploratory analysis of the safety and efficacy of fluoxetine versus lithium monotherapy in individuals with rapid- and non-rapid-cycling bipolar II disorder.


  • Participants included 167 adult patients meeting DSM-IV criteria for bipolar II disorder (by SCID-I/P): 89 women (36.9±12.7 years old) and 78 men (37.9±12.9 years old).  All subjects had recovered from a major depressive episode and experienced minimal current depressive symptoms (Hamilton Depression Rating Scale [HRSD-17] score ≤8). Estimates of the number of prior depressive and hypomanic episodes (defined by DSM-IV criteria) and subsyndromal hypomanic episodes, were obtained.  The participants' condition was classified as rapid cycling if they had an average of ≥4 affective episodes per year during the course of their illness.
  • The study is a randomized, double-blind, placebo-controlled comparison of fluoxetine versus lithium monotherapy in patients initially stabilized on fluoxetine monotherapy. Initial fluoxetine monotherapy 80 mg daily was administered for up to 12 weeks to 37 participants with rapid- and 111 with non-rapid-cycling bipolar disorder. Twenty-five subjects (67.6%) with rapid- and 58 (52.3%) with non-rapid-cycling bipolar disorder recovered with fluoxetine (final HRSD score ≤8) were randomized to long-term monotherapy with either fluoxetine 10–40 mg daily, lithium 300–1200 mg daily (with a serum level of 0.5–1.5 mmol/l), or placebo for 50 weeks.
  • The HRSD, Young Mania Rating Scale (YMRS) and mood conversion measures were obtained at baseline (i.e. randomization) and during double-blind therapy.  The primary outcome measure was the proportion of participants with rapid- v. non-rapid-cycling bipolar disorder with relapse or recurrence of a major depressive episode. Secondary outcomes included the risk of depressive relapse, change over time in YMRS scores (in patients experiencing change in YMRS scores) and frequency of syndromal and subsyndromal mood conversion episodes.



Rapid Cycling

Non-rapid Cycling

P value

Depressive Relapse

9 (36%)

29 (51.8%)


Relapse with:  

   - Fluoxetine
   - Lithium
   - Placebo







Odds of depressive relapse

No significant difference; OR=0.6, 95%, CI 0.2-1.8





No significant difference




YMRS change

No significant difference

Conclusions: In this study of rapid- and non-rapid-cycling subjects with bipolar disorder type II, the rates of depressive relapse and syndromal and subsyndromal hypomania were similar during long-term lithium and fluoxetine monotherapy and placebo.

Clinical Commentary
Most current treatment guidelines advise against the use of antidepressant monotherapy (without concomitant therapy with a mood stabilizer) in bipolar disorder, especially for patients with rapid-cycling bipolar disorder. The current report appears to challenge this expert consensus: the authors report that patients with a history of rapid-cycling bipolar II disorder show no increased risk of affective switches during 50 weeks of fluoxetine monotherapy (compared to lithium monotherapy). Before deciding to discard the current treatment guidelines in bipolar disorder, it is useful to note several details. First, the classification of “rapid cycling” in this study involved an average of 4 or more syndromal or subsyndromal episodes per year during the course of their illness (not in the past year, as per DSM-IV-TR criteria). Some of the subjects designated as rapid cycling in this study may have had fewer episodes in the last year compared to the non-rapid cycling subjects. In the rapid-cycling group the most recent depressive episode was 13.3 months, which is not consistent with current rapid cycling. Second, all subjects randomized to lithium or fluoxetine had previously tolerated a 12-week course of high dose (80 mg) fluoxetine monotherapy.  Since only subjects stable at the end of the initial treatment entered the randomized phase of the study, we can conclude these subjects represent a subgroup of patients pre-selected for their ability to not experience affective shifts during fluoxetine monotherapy. On balance, the current study importantly highlights the existence of a subgroup of subjects with bipolar disorder type II which may tolerate and experience good outcomes on long-term fluoxetine monotherapy. This usefully challenges the dogma of always avoiding antidepressants in bipolar subjects. However, the specific design of the study prevents us from generalizing these results to the entire population of subjects with bipolar II disorder (and especially those bipolar subjects with recent rapid-cycling).



The Sertraline vs Electrical Current Therapy for Treating Depression Clinical Study: Results From a Factorial, Randomized, Controlled Trial

Brunoni AR, Valiengo L, Baccaro A, et al
JAMA Psychiatry. 2013;70(4):383-391. 

The aim of this study was to assess the efficacy and safety of transcranial direct current stimulation (tDCS) compared to a standard SSRI antidepressant (sertraline) in subjects with major depressive disorder (MDD). 


  • Participants were 120 subjects meeting DSM-IV criteria for nonpsychotic, unipolar MDD (diagnosed with the MINI structured interview).  All subjects were antidepressant-free and had moderate to severe depressive symptoms (HRSD-17 score ≥ 18). Most subjects had low level of treatment resistance.
  • Participants were randomized using a 2×2 factorial design to sertraline/placebo and active/sham tDCS, constituting 4 groups: 1) sham tDCS and placebo (sham+placebo); 2) sham tDCS and sertraline (sertraline only); 3) active tDCS and placebo (tDCS only); and 4) active tDCS and sertraline (combined treatment).  
  • Active and sham tDCS were administered as twelve 30-minute tDCS sessions (10 consecutive tDCS sessions, Monday to Friday, in the first 2 weeks, then 2 additional sessions at 2 and 4 weeks).
  • The tDCS montage involves 2 electrodes places over the forehead: the anode over the F3 and the cathode over the F4 areas (according to the International 10-20 EEG electrode positioning system). These electrode positions correspond to the left and right dorso-lateral prefrontal cortex (DLPFC). 
  • For active tDCS a direct current of 2 mA was applied for 30 minutes at each session. 
  • Sham tDCS used the same montage but the device was turned off after 1 minute of stimulation (mimicking a mild local scratching sensation to preserve blinding).
  • The pharmacological intervention was a fixed dose of sertraline 50 mg/d or placebo.
  • The primary outcome measure was the change in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to 6 weeks (end point).


Treatment Group

Mean Difference in MADRS Scores Compared to Sertraline + tDCS1

CI; P Value

Sertraline 2

8.5 points

95% CI, 2.96 to 14.03; P=.002


5.9 points

95% CI, 0.36 to 11.43; P=.03

Placebo+sham tDCS

11.5 points

95% CI, 6.03 to 17.10; P>.001

            1At 6 weeks, the combination of tDCS and sertraline had superior efficacy compared to either treatment alone.
            2 tDCS and sertraline used alone were associated with comparable efficacy (mean difference=2.6 points; 95% CI, -2.90 to 8.13; P=.35.
            3 Active tDCS alone (but not sertraline alone) was superior to placebo+sham tDCS.

      Adverse effects include skin redness on the scalp in active tDCS (P = .03). There were 7 episodes of treatment-emergent mania or hypomania, 5 occurring in the combined treatment group. The integrity of the blinding was problematic: participants correctly guessed both sertraline and tDCS use (although the authors stress that most participants were “only moderately confident in their choices”).

Conclusions: In this group of MDD subjects with low levels of treatment resistance, treatment with tDCS or low-dose sertraline was associated with similar rates of improvement and adverse events. The combination of tDCS and sertraline had superior efficacy compared to either treatment alone or compared to sham. 

Clinical Commentary 
Over the last decade a series of novel devices using different forms of energy for brain stimulation have been proposed as treatment strategies for mood disorders. Transcranial direct current stimulation is an old technology; its efficacy as an antidepressant appears questionable based on poorly designed older studies. This is the first well-designed study testing this treatment, but in a population with very low levels of treatment resistance and in comparison to a low dose of a standard antidepressant. The blinding appears imperfect, which raises additional questions on the full validity of the results. The tDCS treatment is easy to deliver and may be associated with standard antidepressants for additional efficacy. On balance, tDCS appears a valid treatment for milder, non treatment-resistant forms of depression.


Practice-Based Versus Telemedicine-based Collaborative Care for Depression in Rural Federally Qualified Health Centers: A Pragmatic Randomized Comparative Effectiveness Trial

Fortney JC, Pyne JM, Mouden SB, et al
Am J Psychiatry. 2013;170(4):414-425.

Practice-based collaborative care is a complex, evidence-based practice; it is however difficult to implement in smaller primary care practices that lack on-site mental health staff. Telemedicine-based collaborative care may represent a solution, as it allows integration of mental health providers into remote primary care settings. The objective of this multisite randomized comparative effectiveness trial was to evaluate the outcomes of patients assigned to practice-based and telemedicine-based collaborative care. 


  • From 2007 to 2009, 19,285 patients at five federally qualified health centers serving medically underserved populations were screened for depression with the Patient Health Questionnaire (PHQ-9).
  • None of the clinics had mental health staff.
  • 15% (N=2,863) of the patients screened positive (PHQ-9 ≥10). 
  • 364 patients who screened positive were enrolled in the study and followed for 18 months, randomly assigned to one of the two interventions. Most of the subjects in the study were in rural locations, unemployed, and uninsured. 
  • Those assigned to practice-based collaborative care received evidence-based care from an on-site primary care provider and a nurse care manager (nurses with no prior mental health experience who received a 1-day training in depression care management). No mental health provider supervised nurse care managers.
  • Patients assigned to telemedicine-based collaborative care received evidence-based care from an on-site primary care provider and an off-site team: a nurse care manager and a pharmacist by telephone, and a psychologist and a psychiatrist via videoconferencing. In the collaborative care group patients received medication management and CBT (if needed) via videoconference. 
  • The primary clinical outcome measures were treatment response, remission, and change in depression severity.  Follow-up was performed with blinded telephone interviews at 6, 12, and 18 months.



Telemedicine-based Group


Better outcomes for both response and remission

Greater reductions in depression severity over time (Per Hopkins Symptom Checklist)

Higher patient satisfaction with treatment

Note: Improvements in outcomes appears to be attributable to higher fidelity to the collaborative care evidence base
in the telemedicine-based group compared to the practice-based group. 

Conclusions: In the context of small remote primary care practices with no mental health staff, better trained/supervised nurse care managers obtain superior outcomes via telemedicine compared to minimally trained local part-time care managers with no additional supervision from mental health professionals and pharmacists.

Clinical Commentary
The effectiveness of collaborative care programs in the treatment of depression in primary care has been supported by several previous studies. However, in most previous studies collaborative care involved local care managers and mental health specialists. The current study has important implication for the organization of collaborative care in remote settings lacking local mental health providers. For such settings, the current study suggests that centralized care management using full-time managers supervised by specialists yields superior outcomes, even if such care is delivered via teleconference. The benefit of local relationships between patients and providers appears to be surpassed by the higher quality of the care and monitoring delivered as part of the centralized program. 


Contribution of Common Genetic Variants to Antidepressant Response

Tansey KE, Guipponi M, Hu X, et al
Biol Psychiatry. 2013;73(7):679-682.

The field of pharmacogenetics assumes that drug responses are heritable traits.  However, whether an individual’s response to a given drug is heritable has not, in general, been established.  The aim of this study was to estimate the heritability of response to antidepressants, by combining genetic data and clinical outcome data after treatment with SSRI or SNRI antidepressants from two large studies in MDD.


  • The authors have combined two large samples of adults with MDD, with prospectively recorded outcome of antidepressant treatment and genome-wide genotyping were used in this analysis, the Novel Methods Leading to New Medications in Depression and Schizophrenia (NEWMEDS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D). 
  • NEWMEDS includes 2146 individuals with available blood DNA, treated with SSRI (escitalopram, citalopram, paroxetine, sertraline, fluoxetine) or NRI (nortriptyline, reboxetine) antidepressants for 6-12 weeks.  STAR*D included 1,948 MDD subjects with available blood DNA treated for up to 14 weeks with the SSRI citalopram.
  • Unrelated Caucasian individuals (n=1,790 from NEWMEDS and n=1,107 from STAR*D) who passed stringent genotype quality control were included in the analyses. 
  • Antidepressant response was defined as a continuous variable [ie, change from baseline in depression severity on the primary depression rating scale (MADRS, HAMD)], adjusted for age, sex, and recruiting center/study.
  • Heritability was estimated with a novel method (Genome-wide Complex Trait Analysis, GCTA), which uses genome-wide single-nucleotide polymorphisms (SNPs) to estimate directly the total additive genetic variance. GTCA approach compares how similar pairs of individuals are both genetically (lining up many SNPs across the genome) and phenotypically (in terms of response to antidepressants) to estimate heritability. If a trait is heritable, then individuals who are genetically more similar should also be phenotypically more similar. The analyses were restricted to 71,297 autosomal SNPs that were common across the two genotyping platforms used in the two studies. These SNPs were evenly spread out across the genome and covered all autosomes.


  • The additive effects of common genetic polymorphisms across the human genome explain approximately 42.0% (SE=.180, P=.009) of individual variation in response to antidepressants.
  • In 2,273 subjects treated with SSRI antidepressants, common SNPs explained .428 (SE=.230) of variance in response to serotonergic antidepressants.
  • The similar estimates for all antidepressants and for SSRI antidepressants suggest that most of the genetic contribution is common between SSRI and NRI antidepressants.
  • This estimate of variance of antidepressant response explained by common genetic variation, together with the lack of any positive genome-wide association studies suggests that antidepressant response is a polygenic trait with a contribution from multiple common genetic variants across the genome, similar to other complex traits, such as schizophrenia.

  These results suggest that response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect. 

Clinical Commentary
Multiple previous pharmacogenetics studies have tried to detect genetic markers of antidepressant response, with very limited results so far. The current report suggests that a significant (42%) proportion of the variance in antidepressant response may be related to genetic factors.  However, the data implicate a high number of common genetic variants scattered across the genome, none of which have very large effects, but cumulatively contribute to a substantial proportion of variation.  This makes more unlikely the possibility of a simple genetic test to predict antidepressant response in clinical populations. Moreover, these data do not imply that one could explain 42% of the variability in antidepressant response, or have 42% accuracy, in a very complex genetic test taking into account all the SNPs highlighted by on these data; the accuracy of such genetic tests may be significantly lower.  This report is definitely not the final word on this subject and future studies, with even larger samples, may focus our understanding of genetic predisposition for antidepressant response on a narrower group of genes.  However this is a sobering result, which highlights the difficulty of finding a genetic test to accurately predict antidepressant response in clinical populations.


Lithium, Gray Matter, and Magnetic Resonance Imaging Signal
Cousins DA, Aribisala B, Nicol Ferrier I, et al
Biol Psychiatry. 2013;73(7):652-657.

Objectives: Multiple previous magnetic resonance imaging (MRI) studies have reported that lithium can increase the volume of gray matter or the thickness of cortical layers in the human brain.  This finding has been interpreted as the result of neurotrophic or neuroprotective effects of the drug (which have also been detected in animal models).  The current study has tested an alternate hypothesis, that lithium may influence directly the intensity of the MRI signal and that reported changes in gray matter volumes may be artifacts resulting from the altered image contrasts. This hypothesis was tested by measuring gray matter volume change after a short course of lithium with two neuroimaging methods: voxel-based morphometry and Structural Image Evaluation using Normalization of Atrophy (SIENA). 


  • Participants were 32 healthy young men. Subjects with psychiatric or medical conditions were excluded. In study 1, eight subjects received MRI before and after 11 days of open-label lithium to detect the effects of lithium on proton relaxation times and on the brain MRI volumetric analysis. In study 2, MRIs were performed at baseline and after a course of high-dose lithium (n=9), low-dose lithium (n=9), or placebo (n=6). In all instances, anatomical and quantitative scan data were acquired before medication administration and after 11 days of lithium.
  • All scans were performed on 3 Tesla Achieva whole-body scanner (Philips Medical Systems) with an 8-channel SENSE head coil. The protocol comprised: 1) high-resolution three-dimensional (3D) T1-weighted anatomical (repetition time [TR] = 9.6 msec; echo time [TE] = 4.6 msec; flip angle = 8°; field of view = 240×240 mm; contiguous); 2) fast quantitative T1 measurement with a custom inversion recovery prepared echo-planar imaging sequence (TR = 15 sec; TE = 24 msec; inversion time = .25–2.5 sec in 12 uniform steps; matrix 128×128, 72 slices, isotropic 2-mm resolution); and 3) low-resolution Bo field-map with a dual echo 3D gradient-echo (TR = 27 msec, TE = 2.6, 6.1 msec).
  • Image analysis was performed on a Linux platform using several software packages (MATLAB; SPM8; MRICRO; FSL).  To perform voxel-based morphometry (VBM), T1-weighted anatomical images were normalized and segmented with a three-compartment model in SPM8 (gray matter/white matter/CSF).  Global volumes for gray matter, white matter, and cerebrospinal fluid (CSF) were calculated by summing the voxel intensity values over each segmented image. 
  • The fully automated Structural Image Evaluation using Normalization of Atrophy (SIENA) software was also used to measure brain volume change between baseline and endpoint scans. SIENA estimates volume change by finding the brain/non-brain edge points on images and then measuring the perpendicular edge displacement between baseline and endpoint scans for each subject. The mean edge displacement is converted into a global estimate of percentage brain volume change.
  • Quantitative T1 relaxometry analysis was also performed. 




Lithium (11 days)


Placebo (11 days)


P Value

Grey Matter Volume:

Voxel–based Morphometry


No change


Grey Matter Volume:


No change

No change


Grey Matter
T1 Relaxation


No change


Conclusion: Magnetic resonance images of the brain differ before and after a short course of lithium, but this difference might derive from a change in the characteristics of the MRI signal rather than an actual increase in gray matter volume.

Clinical Commentary
Lithium remains the gold standard in the treatment of bipolar disorder. However, its clinical effects occur over longer periods of treatment.  Multiple studies have highlighted neurotrophic or neuroprotective effects of lithium in animals, while high-definition MRI studies have reported significant increases in gray matter volume even after relatively brief periods of lithium treatment (several weeks). The current report raises the likelihood that such significant increases in gray matter volume after short periods of lithium treatment probably represent an artifact. This should not change our enthusiasm for using lithium for bipolar subjects, but it puts in perspective simplistic biological “explanations” of lithium efficacy.


The Association Between Low Vitamin D and Depressive Disorders

Milaneschi Y, Hoogendijk W, Lips P, et al.
Molecular Psychiatry advance online publication 9 April 2013; doi: 10.1038/mp.2013.36

Objective:  It has been hypothesized that hypovitaminosis D is associated with depression but epidemiological evidence supporting this assertion is limited and contradictory. This study investigated the association between depressive disorders and related clinical characteristics with blood concentrations of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in a large cohort of depressed patients, subjects with remitted depression and healthy controls. Associations between serum 25(OH)D and specific clinical features and the course of illness in  currently depressed subjects were also tested.


  • Participants were part of the Netherlands Study of Depression and Anxiety (NESDA). Between 2004–2007, 2981 participants aged 18–65 years (including subjects with a current or past depressive and/or anxiety disorder and healthy controls) were recruited from the community (19%), general practice (54%), and secondary mental health care (27%).  After 2 years, a face-to-face follow-up assessment was conducted (response rate= 87.1%). At baseline, participants provided blood samples and underwent medical examinations and psychiatric interviews. 
  • DSM-IV diagnoses of depressive and anxiety disorders were ascertained with a structured interview (Composite Interview Diagnostic Instrument, CIDI).  
  • Vitamin D analyses were performed in 2,386 participants with a current (ie, within the past 6 months; N=1,158) or remitted (ie, lifetime, but not current; N=815) depressive disorder and healthy controls (N=511). 
  • Analyses on the course of depressive disorders were based on 902 participants depressed at baseline who participated in the 2-year follow-up.
  • Vitamin D status was measured by assessing circulating levels of 25(OH)D, which is the combined product of cutaneous synthesis from solar exposure and dietary sources. Fasting blood samples were obtained in the morning around 8 am and kept frozen at −80 °C and never thawed before analysis. Serum 25(OH)D was measured using isotope dilution—online solid phase extraction liquid chromatography–tandem mass spectrometry (ID-XLC-MS/MS).  
  • Serum intact PTH was determined using an immunometric assay (Abbott Laboratories, Abbott Park, Illinois).
  • Clinical characteristics measured for subjects with current depressive disorders:
    • Severity of depression (28-item self-report IDS)
    • Depressive symptoms duration during the past 4 years (Life Chart Interview)
    • Age of onset and presence of comorbid anxiety disorders (from the CIDI) and use of medications including antidepressants.
    • Course of depressive disorders was determined using two different outcome measures: (1) the presence (yes/no) of a DSM-IV depressive diagnosis (past 6-months) at 2-year follow-up; (2) duration of depressive symptoms over 2 years (derived from the Life Chart Interview).
    • Duration of symptoms was calculated as the percentage of time during follow-up with symptoms of at least mild severity.   
  • Putative confounders, selected a priori on the basis of previously reported associations with vitamin D and depression, included:
    • Sociodemographic variables (age, sex, and years of education)
    • Smoking status and alcohol use
    • Body mass index (BMI) and physical activity
    • The number of chronic diseases for which subjects received treatment (eg, cardiovascular disorders, diabetes, lung disease, arthritis, cancer, ulcer, intestinal problem, liver disease, epilepsy, and thyroid gland disease)
    • Use of vitamin D supplements
    • The number of sunlight hours in the 10 weeks preceding blood drawing
    • The degree of urbanization (number of inhabitants per km2).


 Depressed Patients

P value, Statistics

Lower 25 (OH)D levels compared with controls

P=0.001, Cohen’s d=0.21

Lowest 25 (OH)D levels in those with most severe depression

P=0.001, Cohen’s d=0.44

Inverse relationship between vitamin D status and:
    -     Symptoms severity

-          Risk of depressive disorder at 2-year follow-up



P=0.003, β=−0.19, s.e.=0.07,

P=0.03, Relative risk=0.90, 95% CI=0.82–0.99

Conclusions: This large cohort study indicates that low levels of 25(OH)D were associated to the presence and severity of depressive disorder, suggesting that hypovitaminosis D may represent an underlying biological vulnerability for depression.

Clinical Commentary
Low levels of vitamin D are relatively common in the general population, especially at northern latitudes and during winter months. This large study has the merit of carefully assessing the association between vitamin D levels and depression while taking into account a host of possible confounders, including sociodemographic factors, sunlight, urbanization, lifestyle and health. As such, the association reported appears credible: low serum vitamin D levels were found in subjects with both current and remitted depression, and among currently depressed patients lower vitamin D levels were associated with a less favorable course. This study lends credibility to previously reported results on the efficacy of vitamin D supplementation in the treatment of depression. Of note, this cross sectional study does not inform on the directionality of this association. It is possible that low vitamin D levels may trigger depression, but it is also possible that changes in lifestyle associated with depression (obesity, staying indoors and avoiding sunlight, etc.) may result in lower vitamin D levels. However, given the inexpensive and generally benign nature of vitamin D supplementation, these data justify future efforts to study the role of vitamin D supplementation as part of preventive or treatment interventions in major depression. 



GME Research Review

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.


ISSUE 13, April 2013 — Guest Commentator: M. Zachary Rosenthal, PhD, Duke University Medical Center, Durham, NC 


From Negative to Positive and Back Again: Polarized Affective and Relational Experience in Borderline Personality Disorder

Coifman KG, Berenson KR, Rafaeli E, et al
J Abnorm Psychol. 2012;121(3):668-679.

Objectives: The purpose of this study was to explore the polarity of affective and relational experience (ie, feeling all good or all bad; Beck, Freeman, & Davis, 2004; Kernberg, 1975; Linehan, 1993) over the course of a 21-day experience-sampling diary in adults with borderline personality disorder (BPD) and a comparison group of healthy adults. Additionally, this study investigated the association between the polarity of affective and relational experience and impulsive/maladaptive behaviors commonly exhibited among individuals with BPD. 


  • Participants consisted of 61 healthy controls (Mean age: 33.69 years; 74% female) and 65 individuals with BPD (Mean age: 32.35 years; 82% female).
  • Participants were selected using structured diagnostic interviews (ie, Structured Interview for the Diagnosis of Personality Disorders [SID-P-IV; Pfohl et al, 1997] and the Structured Clinical Interview for DSM-IV [APA, 2000]).
  • Participants were trained to use a personal digital assistant (PDA) in order to complete the experience-sampling diary. The PDA used a 5x/day random signaling schedule to assess state affect (eg, disappointed, tense, afraid, sad, angry, satisfied, energetic, happy, enthusiastic, calm), relational experiences (eg, how content they were with an important person in their lives, how cared for they felt by this person, how irritated and angry they were with this person, etc), and behaviors (eg, excessive spending, binge eating, risky sexual behavior, substance use, and self-injury).
  • The mean number of completed entries for the entire sample was 74, SD=20.66 (71% compliance), with no significant group differences in the number of entries completed.  Researchers applied multilevel modeling techniques (Rafaeli, Rogers, & Ravelle, 2007) to capture the within-person covariance of momentary reports of negative and positive features of experience, either affective or relational.

Data indicated significantly greater polarity in reports of affective and relational experiences in BPD that increased during heightened interpersonal stress. Researchers also examined the association of affective and relational polarity to reports of impulsive behaviors (eg, self-injury, substance use, etc.) and found evidence that increased polarity in reports of affective (in low-stress contexts) and relational experiences (in high-stress contexts) predicted increased rate of reports of impulsive behaviors.

Conclusions: Compared to psychiatrically healthy adults, individuals with BPD are more likely to demonstrate polarity of both affective and relational experiences when these phenomena are repeatedly measured over time. Polarity in reported affective and relational experience is associated with increased frequency of risky and impulsive behaviors. The results support contemporary models of interpersonal functioning in BPD suggesting that treatment should decrease extremes in affect and in ways of thinking about others.

Clinical Commentary
By using experience sampling over a 3-week time frame, this study provides empirical data to support clinical observations that individuals with BPD are often extreme in their ways of thinking about others, and in experiencing affect. Importantly, this study also points to the critical link between polarity in affect and relational experience and common impulsive behavior among individuals with BPD. The use of structured interviews, a prospective design and multi-level modeling, are methodological strengths. A next step in this area of research might be to move beyond comparison of individuals with BPD to healthy controls, by adding other clinical comparison groups. Such research would better characterize the relationships among interpersonal stress, affect, and relational functioning in BPD, specifically, compared to other clinical groups. In addition, the present study provides a terrific framework for future researchers to more precisely examine the mechanisms which predict the dynamic unfolding of affective and relational polarity. Understanding the predictors and temporal course of these phenomena will be an important next step in developing novel interventions designed to improve interpersonal functioning in BPD.   


Hypersensitivity in Borderline Personality Disorder During Mindreading

Frick C, Lang S, Kotchoubey B, et al
PLoS ONE. 2012;7(8):e41650

: This study used behavioral and functional neuroimaging methods to examine interpersonal sensitivity (ie, accuracy identifying others’ affective states) among individuals with borderline personality disorder (BPD) and healthy controls. Individuals with BPD have been shown to have impairments in the ability to mentalize (ie, accurately identify others’ mental states), yet in some studies have exhibited enhanced abilities in identifying affective states in others. This study was designed to help clarify whether interpersonal hypersensitivity is  characteristic of BPD and to elucidate the underlying neural structures associated with this interpersonal process. 


  • Sample included 21 non-medicated right-handed female BPD patients and 20 female healthy volunteers recruited from the general population.
  • Questionnaires included SCID-I & SCID-II, Affective Lability Scale (ALS), BDI, and the Edinburgh Handedness Inventory (EHI).
  • Procedure of the RMET as follows:
    • Participants were presented with 36 black-and-white original pictures of eye gazes (12 negative, 8 positive, and 16 neutral stimuli) from the RMET paradigm. Thereafter, participants were required to choose one out of four words (three distracter words and one correct word) that describe the mental state of the person in the photograph seen before as quickly and accurately as possible.
    • Participants were given a short practice, then the experimental procedure started. Each 25-s trial consisted of a 4–6 s jittered fixation cross, a 5-s presentation of a RMET picture (negative, positive, or neutral), a 10-s rating period and again a 4–6-s jittered fixation cross.
    • Image acquisition: Blood Oxygenation Level-Dependent (BOLD) images were obtained on a 3 Tesla MRI scanner (TRIO, Siemens Medical Systems, Erlangen, Germany) system equipped with a 12-channel head coil.



Female Subjects with BPD (N=21)

Healthy (Female) Controls (N=20)



  • - Correct response rate higher than HC in both positive and negative RMET conditions**
  • - Faster than HC in both conditions (fastest for positive gazes, slowest responses for negative eye gazes)**




Negative v neutral

Greater activity in:


  • - Left amygdala
  • - Temporal cortex
  • - Left prefrontal cortex
  • - Right hippocampus
  • - Left parietal cortex
  • - Left occipital cortex

Positive v neutral

Greater activity in:


  • - Left temporal cortex
  • - Prefrontal cortex
  • - Occipital cortex

Negative v neutral

Greater activity in:


  • - Left insula
  • - Temporal cortex
  • - Prefrontal cortex

Positive v neutral

Greater activity in:


  • - Temporal cortex
  • - Prefrontal cortex
  • - Right thalamus
  • - Right occipital cortex



Negative condition

Greater activity in:


  • - Left amygdala
  • - Left temporal pole
  • - Medial frontal gyrus
  • - Right middle temporal gyrus
  • - Left precuneus
  • - Left middle occipital gyrus

Positive condition

Greater activity in:


  • - Right amygdala
  • - Left temporal pole
  • - Left orbitofrontal gyrus
  • - Medial frontal gyrus
  • - Right middle temporal gyrus
  • - Left superior temporal gyrus
  • - Left middle temporal gyrus

Negative condition

Greater activity in:


  • - Right insula
  • - Right inferior frontal gyrus
  • - Right superior temporal pole

Positive condition

Greater activity in:


  • - Insula
  • - Right medial frontal gyrus
  • - Right superior temporal pole
  • - Left parietal lobe
  • - Right posterior cingulate gyrus
  • - Left postcentral gyrus
  • - Right middle temporal gyrus
  • - Right hippocampus

Conclusions: BPD patients demonstrated superior mental state discrimination in a standardized behavioral measure than healthy controls. The results of the present study support the hypothesis of Krohn, which suggests that individuals with BPD have enhanced mentalizing abilities in spite of problems in social relationships. Activation in the amygdala, left temporal pole, and left inferior frontal gyrus in combination provides indirect support to the notion that BPD patients may “resonate” with others’ mental state in their own emotional response. This would provide an intuitive emotional evaluation of others without reflexive awareness and top-down elaborative processing.

Clinical Commentary
This study helps explain the conflicting results in the literature concerning BPD and the discrimination of others’ mental states, or mentalization. Consistent with some previous research, the study findings lend further credence to the clinical observation that patients with BPD may be especially sensitive to others’ affective states. The authors reported that individuals with BPD have a more innate, automatic connection to the emotional states of others than healthy controls. The paper focused on three brain regions as evidence of this apparent ability to “resonate” with the mental states of others. This is an interesting study that has taken an important incremental step in this area of research. Understanding patterns of neural activation during clinically relevant interpersonal processes such as mentalization is critical to the development of next-generation interventions for BPD. One next step that could emerge from this research might be to examine neural and behavioral processes that dynamically unfold downstream following the identification of others’ affective states. Such research would help to characterize vulnerabilities in interpersonal processes that emerge after initial mental state discrimination of others. Additionally, clinically relevant contextual factors (eg, social rejection) need to be incorporated into the design of future studies on this topic in order to enhance the ecological validity of such research.


Physiological and Self-Assessed Emotional Responses to Emotion-Eliciting Films in Borderline Personality Disorder

Elices M, Soler J, Fernandez C, et al
Psychiatry Res. 2012;200(2-3):437-443.

According to Linehan's biosocial model, the core characteristic of borderline personality disorder (BPD) is emotional dysregulation. Most studies have found that patients with BPD report greater self-reported intensity of negative emotions compared to healthy controls. However, emotional hyperreactivity in BPD patients has not been consistently observed in experimental studies. Further, reactivity to discrete emotional stimuli has not been sufficiently assessed among individuals with BPD. Although several studies have examined emotional processes in BPD, most have attempted to induce broad affective states (positive or negative; Rosenthal et al., 2008). Moreover, few studies have assessed emotional responses to positive emotions. In these two experiments, researchers investigated two components of Linehan's model of emotional dysregulation in BPD: baseline emotional intensity and emotional reactivity.


  • Participants: A total of 60 women, 30 with BPD diagnosis and 30 age- and sex-matched healthy subjects (HCs). All participants were Spanish-speaking Caucasians.
    • Inclusion criteria for the BPD subjects: (a) female ages 18 to 45; and (b) a diagnosis of BPD according to DSM-IV criteria as assessed by two semi-structured diagnostic interviews (SCID-II; Gómez-Beneyto et al,1994, and DIB-R; Barrachina et al, 2004). Exclusion criteria for the BPD subjects: (a) acute psychotic episode, or current affective or eating disorders according to DSM-IV criteria; (b) current substance misuse or dependence; and (c) severe physical conditions, eg, heart or respiratory illness, neurological disease, or brain injury.
    • Procedures: In the first experiment, BPD patients were compared to healthy controls (HC) to evaluate emotional responses to six emotion-eliciting film clips, each of which was created to elicit one of the following six discrete emotions: anger, fear, disgust, sadness, amusement, and a neutral state. Skin conductance level, heart rate, and subjective emotional response were recorded during each film clip.
      • First, participants completed the Positive and Negative Affect Schedule (PANAS) to assess baseline self-reports of emotional intensity. Then, the following steps were repeated for each film clip and each subject: (a) baseline physiological measures were recorded for 1 min; (b) the emotion-eliciting film was presented; and (c) subjects self-reported present affective states.
      • In the second experiment, the same groups were compared to evaluate emotional reactions to films containing content on sexual abuse, emotional dependence, and abandonment /separation, all of which are associated with clinical features of BPD.
        • Procedures for the second experiment were the same as in the first, except that only three films (with BPD-related content) were shown.
        • Measures: The MSI-BPD (Zanarini et al, 2003), which consists of 10 true/false questions, was used as a screening instrument for BPD in HCs; PANAS (Sandín et al, 1999), which measures affect state through 20 items, 10 for Positive Affect (PA) and 10 for Negative Affect (NA); Self-Assessment Manikin (SAM; Bradley and Lang, 1994), which evaluates three major affective dimensions: pleasure, arousal, and dominance; and Discrete Emotions Questionnaire (DEQ; Rottenberg et al., 2007), which consists of 18 items that target various emotional states. Physiological data were recorded using the Biofeedback X-pert 2000.
        • Emotional stimuli: A set of emotion-eliciting film clips that had been previously validated in a Spanish sample (PIE; Fernández, et al, 2011). 


  • Experiment 1: Baseline scores: Subjects with BPD had higher baseline scores on the Negative Affect Scale and lower scores on the Positive Affect Scale [F(1,53)=24.9, P<.001; F(1,58)=8.6, P=.005, respectively]. However, physiological activation at baseline showed no significant differences between groups.
  • Compared with HCs, individuals with BPD presented a lower increase in HR for fear [M=18.9, SD=17.4 vs M=11.2, SD=7.9; F(1,58)=4.7, P=.034], sadness [M=15.9, SD=17.3 vs M=8.9, SD=6.9; F(1,58)=4.1, P=.048] and anger films [M=15, SD=10.7 vs M=10, SD=8; F(1,59)=4.11, P=.047].
  • For DEQ scores, a 6×5×2 (respectively: six emotions by five DEQ emotional labels by two groups) repeated measures ANOVA was performed. A significant main effect [F(24,751)=1.8, P=.015] was found and a significant group effect for amusement [F(1,55)=5.8, P=.019] and disgust films [F(1,55)=4.5, P=.039]. Post hoc analyses for the amusement film showed no significant differences between groups for DEQ amusement label score but BPD subjects presented significant higher scores on the DEQ anger label [F(1,58)=9.5, P=.003] and the DEQ disgust label [F(1,58)=6.1, P=.017].
  • Experiment 2: Baseline scores: As in Experiment 1, PANAS scores were significantly different between groups, but baseline physiological activation was not significantly different between groups.
  • For DEQ scores a 3×5×2 (respectively: three BPD-related stimuli by five DEQ labels by two groups) repeated measures ANOVA was performed. Results showed a main effect [F(12,602)=2.1, P=.016] and a group effect for sexual abuse [F(1,51)=21.3, P<.001] and emotional dependence films [F(1,51)=13.2, P=.001].
    • For the sexual abuse film, post-hoc analyses showed that BPD subjects presented significantly higher scores for the anger [F(1,54)=5.4, P=.024], disgust [F(1,54)=10.2, p=0.002], fear [F(1,54)=20.1, P<.001] and sadness [F(1,54)=5.9, P=.019] labels of the DEQ.
    • For the emotional dependence film, post-hoc analyses showed significant differences in disgust [F(1,53)=4.8, P=.034], fear [F(1,53)=9.3, P=.004] and sadness [F(1,53)=7.6, P=.008] labels of the DEQ.
    • For DEQ scores, an effect of history of sexual abuse was only observed for the fear label [BPD with sexual abuse M=4.2, SD=2.5; BPD without sexual abuse M=1.7, SD=1.2; HCs M=2.2, SD=1.2; F(2,53)=4.2, P=.02], where BPD subjects with a history of sexual abuse presented significantly higher scores compared to BPD patients without a history of sexual abuse and HCs.

Although self-reported negative emotions at baseline were stronger in the BPD group, physiological measures showed no differences between the groups. BPD subjects demonstrated no subjective heightened reactivity to most of the discrete emotion-eliciting films. However, subjective responses to amusement and “BPD-specific content” films revealed significant between-group differences. These findings are consistent with previous research and suggest that emotional intensity appears to be a core characteristic of BPD. In contrast, generalized heightened emotional reactivity across stimuli did not characterize the BPD sample in this study.

Clinical Commentary
This study examined two aspects of Linehan’s (1993) biosocial model of BPD: (1) baseline emotional intensity and (2) emotional reactivity. The results are very clinically relevant. Although BPD patients have traditionally been conceptualized as “more reactive,” this study suggests stronger emotional intensity prior to affective cues may better characterize the emotional dysfunction in BPD than generally heightened emotional reactivity. It is important to note that this study and others before it have found some evidence pointing to the role of contextual factors in the elicitation of emotional reactivity in BPD. For example, BPD-specific emotional triggers related to traumatic personal history may be likely to differentially elicit negative affect in BPD. Next-generation interventions for BPD targeting emotional dysfunction need to be developed to directly reduce general emotional intensity. However, it is premature and inappropriate to abandon the idea that emotional reactivity is not relevant in BPD. Instead, the specific contextual factors among individuals with BPD that differentially predict the onset of emotional reactivity need to be better characterized.


The Role of Experiential Avoidance in the Association Between Borderline Features and Emotion Regulation in Adolescents

Schramm AT, Venta A, Sharp C.
Personality Disorders: Theory, Research, and Treatment. 2013; Feb 11. doi: 10.1037/a003189. [Epub ahead of print]

Objective: Difficulties in emotion regulation are a core feature of borderline personality disorder (BPD). Individuals with BPD also report higher levels of experiential avoidance (EA) compared to controls. These constructs have never been studied concomitantly in adolescents. First, given the conceptual similarity of difficulties in emotion regulation and EA, the authors sought to determine whether EA provides incremental validity, above emotion dysregulation, in its association with borderline features. Second, EA was explored as a mediator in the relationship between difficulties in emotion regulation and borderline features.


  • 208 adolescents ages 12­-17 were recruited from an inpatient psychiatric unit for severe behavioral, psychiatric, or substance abuse disorders.
  • Exclusion criteria included psychotic disorders, autism spectrum diagnosis, or an IQ <70 (measured by the Wechsler Adult Intelligence Scale (WAIS).
  • Borderline features were measured using the 24-item self-report Borderline Personality Features Scale for Children (BPFSC).
  • Experiential Avoidance was measured using the 17-item self-report Avoidance and Fusion Questionnaire for Youth (AFQ-Y).
  • Difficulties with Emotion Regulation were measured using the Difficulties with Emotion Regulation Scale (DERS).
  • Internalizing and Externalizing Symptoms were measured using the 112-item Youth Self-Report (YSR) questionnaire.
  • Pearson correlations were used to establish a relationship between variables of interest, and hierarchical linear regression was used to determine whether EA predicts borderline features over and above emotion dysregulation.



Adolescent Inpatients (N=208)



Borderline features, experiential avoidance, and difficulties with emotion regulation were all significantly positively correlated.

Hierarchical Regression

Experiential avoidance made an independent incremental contribution in its association with borderline features, above and beyond difficulties with emotion regulation, gender, and internalizing and externalizing symptoms.

Conclusions: These results support a relationship between EA and BPD features in adolescents, consistent with findings of a relationship between BPD and EA in adults. Further, EA accounted for BPD features in inpatient adolescents over and above emotion dysregulation. Future studies should be conducted to determine whether these results can be replicated in other adolescent samples (eg, in a sample that is not solely inpatients) and using other methods to measure constructs of interest (eg, behavioral, interview).

Clinical Commentary
These results support the growing evidence pointing to experiential avoidance as an important therapeutic target for individuals with BPD features. This is the first study to empirically demonstrate the significance of experiential avoidance to BPD features in an adolescent sample. These results also indicate that experiential avoidance may be distinct, to some degree, from more general difficulties with emotion regulation and may be important to target in therapies for adolescents with BPD features. A next step in this area of research might be to more carefully examine the relationships among EA, emotion regulation difficulties, and BPD symptoms over time using prospective methods from adolescence into adulthood.


Emotional Responses to a Negative Emotion Induction Procedure in Borderline Personality Disorder

Feliu-Soler A, Pascual J, Soler J, et al
Int J Clin Health Psychol. 2013;13:9-17.

: The aim of this study was to determine if patients with borderline personality disorder (BPD) present with higher emotional response than healthy controls in a laboratory setting. Fifty participants (35 patients with BPD and 15 healthy controls) underwent a negative emotion induction procedure (presentation of standardized unpleasant images). Subjective emotional responses and biological reactivity (ie, salivary cortisol and alpha-amylase) were measured at several points during the procedure.


  • Recruited subjects included 28 outpatients with BPD (on medications at the time of the experiment; exclusion criteria for this group included a range of comorbid Axis-I disorders or a current severe medical condition, current psychotherapy, participation in a similar study or knowledge of the study) and 13 healthy control subjects (employees at the hospital, with no Axis-I, Axis-II, or substance abuse)
  • Self-report measures were used to assess depression (measured using the Hamilton Rating Scale for Depression), psychopathology (measured using the Brief Psychiatric Rating Scale), emotional arousal (measured using the Self-Assessment-Manikin), mood state (measured using the Profile of Mood States and the Positive and Negative Affect Schedule), and perceived stress level (measured using the Perceived Stress Scale).
  • Salivary cortisol (sCORT) was used as a measure of subjects’ free fraction (ie, the bioavailable fraction) of blood cortisol and salivary alpha-amylase (sAA) was used as an indirect indicator of SNS activity.
  • Laboratory sessions took place in a set time of day in a set room with consistent temperature and lighting. Subjects were told to wake up before 8 am, and to not take any substances or perform strenuous exercise prior to the study.
  • The emotion-induction stimuli used 24 high activation, negative valence pictures taken from the International Affective Picture System (IAPS).
  • Self-report questionnaires and cortisol samples were taken at four time points: Baseline, Emotional Induction following the first 12 pictures, Emotional Induction following the last 12 pictures, and after completion of the study.




Salivary Cortisol (sCORT)

Salivary alpha-amylase (sAA)



All PANAS and POMS subscales showed significantly higher scores in the BPD group vs HC

The BPD group reported significantly lower SAM-Valence and SAM-Dominance ratings than the control group

Levels of sCORT are lower in BPD group than control group

No significant between-group differences

Emotion Induction


The BPD group reported significantly lower SAM-Dominance ratings than the control group

No significant between-group differences

Levels of sAA significantly higher in BPD group than control group

Emotion Induction 2

The BPD group reported significantly lower SAM-Dominance ratings than the control group

No significant between-group differences

Levels of sAA significantly higher in BPD group than control group


The BPD group reported significantly lower SAM-Dominance ratings than the control group

No significant between-group differences

No significant between-group differences


Conclusions: Consistent with prior research, individuals with BPD reported higher negative emotional intensity at baseline; however, contrary to expectations driven by Linehan’s biosocial model, these findings indicate that individuals in the BPD group did not demonstrate higher emotional reactivity to negative stimuli, nor did they show a distinct pattern of recovery when compared to healthy controls. Specifically, there were no significant between-group differences in self-report or physiological negative affective reactivity. However, this may be due to the low baseline levels of cortisol in the BPD sample. Additionally, elevated sAA in the BPD group does reflect some degree of sympathetic activation; however, further studies using more BPD-specific emotion inductions, different types of emotional induction, and different measures of reactivity are needed to clarify the trends observed in this study. Of note, the emotion-induction measure used was insufficient to induce negative affect in either sample, which complicates the interpretation of these findings.

Clinical Commentary
These findings do not support the idea that individuals with BPD are more generally emotionally reactive to standardized emotional cues. Although future research is required to specify the types of stressors effective at inducing negative emotion in BPD samples, this might point to a contextual specificity in the nature of stressors that will be emotionally arousing to this population. What does seem to set individuals with BPD apart from healthy controls in this study, and in other recent studies, is self-reported negative affective intensity at baseline. It may be useful in future studies to examine the variability of emotional intensity in BPD, and to begin exploring ways to reduce negative emotional intensity in controlled laboratory settings. Identification and optimization of laboratory-based methods to reduce negative emotional intensity in BPD could provide the groundwork needed to help develop new approaches for behavioral interventions.


Components of Emotion Dysregulation in Borderline Personality Disorder: A Review

Carpenter RW, Trull TJ.
J Curr Psychiatry Rep. 2013;15:335. doi: 10.1007/s11920-012-0335-2.

Objectives: Using Linehan's biosocial model, the authors of this review conceptualize emotion dysregulation in borderline personality disorder (BPD) as consisting of four components: emotional sensitivity, heightened and labile negative affect, a deficit of appropriate regulation strategies, and a surplus of maladaptive regulation strategies. Research is reviewed to support and characterize each of these components of emotional dysfunction in BPD.


  • Narrative literature review was conducted on the four core components of emotion dysregulation implicated in Linehan’s biosocial model: (1) emotion sensitivity; (2) negative affect; (3) inadequate emotion regulation strategies; and (4) maladaptive regulation strategies.



Self-Report Evidence

Laboratory Evidence

Ambulatory Findings

Neuroimaging Findings

Emotion Sensitivity
(ie, heightened emotional reactivity to environmental stimuli, including emotions of others)


Demonstrated primarily in association with negative mood states (eg, anger, fear, sadness)

Negative emotionality in early childhood predicts later BPD symptoms (N=162)

Mixed findings in response to emotional Stroop tasks; some report slower reaction times for individuals with BPD and others found no significant differences

Biased toward identifying negative emotions in others

Less accurate in correctly identifying emotions in facial stimuli, overall; findings are mixed.


During an emotional Stroop task, control group showed increased activation in the anterior cingulated cortex (ACC) and frontal lobe, while BPD did not.

Negative Affect


Self-reported intensity and reactivity of negative affect strongly associated with BPD

Intensity and reactivity of negative affect, measured by psychophysiological methods, associated with BPD

Evidence of greater instability of negative affect for BPD patients:

1. BPD patients (N=50) were more unstable on emotional valence and distress than controls (N=50); they were more prone to large decreases in positive mood into negative mood state

2. Compared to MDD patients, BPD patients reported more instability of hostility, fear, and sadness (not positive or negative affect).


Inadequate Emotion-Regulation Strategies
(ie, lack of adaptive strategies)

BPD patients have:

- Lower emotional awareness, clarity, and mood labeling (focused on arousal vs valence) than control subjects

-More problems employing emotion-regulation strategies

-Lower distress tolerance than control subjects

-Less access to effective emotion-regulation strategies

BPD patients have:

- More problems employing emotion-regulation strategies

-Lower distress tolerance than control subjects; those with the lowest distress tolerance showed the strongest association between emotion dysregulation and BPD symptoms.

BPD patients experienced greater polarity (all-or-nothing) in their negative affect

BPD patients have more problems employing emotion regulation strategies

Maladaptive Emotion-Regulation Strategies


Self-reported affective instability, urgency, and lack of premeditation uniquely predicted BPD symptom severity in an undergraduate sample

BPD patients show decreased pain while engaging in self-injury, particularly when distressed

BPD patients in a negative emotional state committed fewer impulsive responses on a passive avoidance learning task than BPD patients not in a negative emotional state


BPD patients demonstrate decreased activation in the ventromedial prefrontal cortex during an emotional go/no-go task requiring behavioral inhibition

BPD patients showed a negative coupling between paralimbic and prefrontal regions after painful stimulation, possibly indicating that prefrontal regions inhibited paralimbic regions following pain

Conclusions: Individuals with BPD show deficits in multiple domains of emotion regulation. Specifically, evidence suggests that individuals with BPD: (1) demonstrate a negative bias when identifying facial expressions of emotion; (2) experience heightened negative affect, particularly affective instability and reactivity; (3) demonstrate low distress tolerance; and (4) are prone to maladaptive emotion regulation strategies such as rumination, thought suppression, experiential avoidance, and impulsive behaviors. Although these findings help highlight the importance of emotion dysregulation in BPD, the continued presence of mixed findings and conflicting evidence points to an underlying issue in definitional clarity in research on emotion regulation in BPD. In order to clarify the particular emotion-regulation deficits relevant to BPD, we require more research that utilize precise, specific terminology to define affective processes and clear methodologies that can help to clarify the contexts in which individuals with BPD do and do not experience difficulty with emotion regulation. 

Clinical Commentary
These findings support the widespread notion that emotion dysregulation is essential to target in any treatment designed for individuals with BPD. One construct that this study highlights as particularly important to address in treatment is distress tolerance. Distress tolerance might provide some protection against BPD symptoms and self-injurious behavior, particularly in those who experience intense negative affect. Another skill that it is particularly important to focus on in therapeutic interventions is building emotion-regulation strategies that the patient feels are effective in managing negative affect. By promoting adaptive emotion-regulation strategies, we can hopefully reduce reliance on maladaptive emotion-regulation techniques such as self-harm. A key point made by the authors is that research in this area must specify clear processes underlying emotional dysregulation. The term emotion dysregulation may be rendered somewhat meaningless if it continues to be used broadly when referring to problems in BPD or in psychopathology more generally. Instead, researchers must discontinue the use of this vague term and replace it with clearly operationalized processes capable of being directly observed.















GME Research Review

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.

ISSUE 12, March 2013 — Guest Commentator: Manpreet K. Singh, MD, Stanford University School of Medicine, Stanford, CA


Antidepressants Normalize the Default Mode Network in Patients With Dysthymia

Posner J, Hellerstein DJ, Gat I, et al
JAMA Psychiatry. 2013;Feb 6:1-10.

Objective: The default mode network (DMN) is a collection of brain regions that reliably deactivate during goal-directed behaviors and is more active during a baseline, or so-called resting, condition. Coherence of neural activity, or functional connectivity, within the brain's DMN is increased in major depressive disorder relative to healthy control (HC) subjects; however, whether similar abnormalities are present in persons with dysthymic disorder (DD) is unknown. Moreover, the effect of antidepressant medications on DMN connectivity in patients with DD is also unknown. This study aimed to use resting-state functional-connectivity magnetic resonance imaging (MRI) to study (1) the functional connectivity of the DMN in subjects with DD vs HC participants and (2) the effects of antidepressant therapy on DMN connectivity.


  • After collecting baseline MRI scans from subjects with DD and HC participants, we enrolled the participants with DD into a 10-week prospective, double-blind, placebo-controlled trial of duloxetine and collected MRI scans again at the conclusion of the study.
  • Enrollment occurred between 2007 and 2011 at a University research institute.
  • Volunteer sample of 41 subjects with DD and 25 HC participants aged 18 to 53 years. Control subjects were group matched to patients with DD by age and sex.
  • We used resting-state functional-connectivity MRI to measure the functional connectivity of the brain's DMN in persons with DD compared with HC subjects, and we examined the effects of treatment with duloxetine vs placebo on DMN connectivity.



Subjects with Dysthymia (N=41)

Healthy Comparison Participants (N=25)

Baseline imaging

Greater coherence of neural activity within the brain’s default mode network (DMN)

Less coherence of neural activity in the DMN

10-week follow-up after treatment with duloxetine (vs placebo)

Normalized DMN connectivity

Typical DMN connectivity

The baseline imaging findings are consistent with those found in patients with major depressive disorder and suggest that increased connectivity within the DMN may be important in the pathophysiology of both acute and chronic manifestations of depressive illness. The normalization of DMN connectivity following antidepressant treatment suggests an important causal pathway through which antidepressants may reduce depression.

Clinical Commentary
Over the past several months, several pharmaco-MRI studies have been published. It is exciting to see that neuroimaging methods are now being applied to assess neural mechanisms of treatment response. The most direct and common way to evaluate the effect of a medication is to use a pre-post dose imaging design. This article examines the functional connectivity of the dysthymic brain during rest and aims to determine whether antidepressants can alter the way in which brain regions are connected at rest. This is the first of such a study to examine individuals with dysthymic disorder, as opposed to major depressive disorder, which already restricts generalizability of the findings to a population with more chronic low-grade depression. In addition, the agent used for treatment was duloxetine, a strange candidate given that we know so little about the neural effects of more commonly prescribed selective serotonin reuptake inhibitors. Nevertheless, the study found similarities between the neural networks in individuals with depression and dysthymia suggesting that increased connectivity within the default mode network may represent a biological indicator of both acute and chronic forms of depression. In addition, this connectivity normalized with duloxetine treatment, providing a potential mechanism of action by which this medication reduces symptoms.


Relationships Between Changes in Sustained Fronto-Striatal Connectivity and Positive Affect in Major Depression Resulting From Antidepressant Treatment

Heller AS, Johnstone T, Light SN, et al
Am J Psychiatry. 2013;170:197-206. 

Objective: Deficits in positive affect and their neural bases have been associated with major depression. However, whether reductions in positive affect result solely from an overall reduction in nucleus accumbens activity and fronto-striatal connectivity or the additional inability to sustain engagement of this network over time is unknown. The authors sought to determine whether treatment-induced changes in the ability to sustain nucleus accumbens activity and fronto-striatal connectivity during the regulation of positive affect are associated with gains in positive affect.


  • Using fMRI, the authors assessed the ability to sustain activity in reward-related networks when attempting to increase positive emotion during performance of an emotion regulation paradigm in 21 depressed patients before and after 2 months of antidepressant treatment.
  • Over the same interval, 14 healthy comparison subjects underwent scanning as well.



Subjects with Depression (N=21)

Healthy Comparison Participants (N=14)

Baseline imaging

Greater ability to sustain activity in reward-related networks within the brain’s frontostriatal circuitry

Lesser ability to sustain activity in reward-related networks within the brain’s frontostriatal circuitry

8-week follow-up  after antidepressant treatment

Largest increases in sustained nucleaus accumbens activity have largest increases in positive effect

None of these associations were observed in healthy comparison subjects


Largest increases in sustained frontostriatal connectivity have largest increases in positive affect when controlling for negative affect

None of these associations were observed in healthy comparison subjects

Treatment-induced change in the sustained engagement of fronto-striatal circuitry tracks the experience of positive emotion in daily life. Studies examining reduced positive affect in a variety of psychiatric disorders might benefit from examining the temporal dynamics of brain activity when attempting to understand changes in daily positive affect.

Clinical Commentary
Here is another pre-post medication pharmaco-fMRI study examining the effects of antidepressants on the depressed brain. The design of the study was based on the assumption that there are deficits in positive affect in depression, but it is unknown whether these deficits are a cause or effect of the disorder. To examine this question, authors assessed the ability of depressed individuals to sustain activity in reward-related networks when attempting to increase positive emotion during an emotion regulation task before and after 2 months of antidepressant treatment. The treatment was nonuniform among individuals in the study, but the results were nevertheless interesting. Those individuals who demonstrated the largest increases in sustained nucleus accumbens activity (a region essential for processing rewarding stimuli) and functional connectivity between the prefrontal cortex and striatum over the 2 months of treatment had the largest increases in positive affect. These findings provide another mechanism by which antidepressants exert their action of improving hedonic drive by targeting the brain’s reward centers.


Predicting Treatment Response in Social Anxiety Disorder From Functional Magnetic Resonance Imaging

Doehrmann O, Ghosh SS, Polli FE, et al
JAMA Psychiatry. 2013;70(1):87-97.

Objectives: Current behavioral measures poorly predict treatment outcome in social anxiety disorder (SAD). To our knowledge, this is the first study aimed to examine neuroimaging-based treatment prediction in SAD to specifically determine whether brain activation in patients with SAD can serve as a biomarker to predict subsequent response to cognitive behavioral therapy (CBT).


  • Functional magnetic resonance imaging (fMRI) data were collected prior to CBT intervention.
  • Changes in clinical status were regressed on brain responses and tested for selectivity for social stimuli.
  • Thirty-nine medication-free patients meeting DSM-IV criteria for the generalized subtype of SAD were treated with protocol-based CBT at anxiety disorder programs at Boston University or Massachusetts General Hospital and underwent neuroimaging data collection at Massachusetts Institute of Technology.
  • Brain responses to angry vs neutral faces or emotional vs neutral scenes were examined with fMRI prior to initiation of CBT.
  • Whole-brain regression analyses with differential fMRI responses for angry vs neutral faces and changes in Liebowitz Social Anxiety Scale score were recorded as the treatment outcome measure.



Subjects with SAD (N=39)

Baseline brain functional responses to angry versus neutral faces or emotional versus neutral scenes.


Treatment outcome: Whole-brain regression with differential fMRI responses to angry versus neutral faces correlated with changes in social anxiety scale score

Pretreatment responses significantly predicted subsequent treatment outcome of patients selectively for social stimuli and particularly in regions of higher-order visual cortex.

Variance accounted for by combining neuroimaging with clinical measures versus clinical measures alone

Combining the brain measures with information on clinical severity accounted for more than 40% of the variance in treatment response and substantially exceeded predictions based on clinical measures at baseline.  Prediction success was unaffected by testing for potential confounding factors such as depression severity at baseline.

 The results suggest that brain imaging can provide biomarkers that substantially improve predictions for the success of cognitive behavioral interventions and more generally suggest that such biomarkers may offer evidence-based, personalized medicine approaches for optimally selecting among treatment options for a patient.

Clinical Commentary
This article examines the differential fMRI responses for angry versus neutral faces in socially anxious individuals before and after cognitive-behavioral therapy. This extends our theme of neural mechanisms of treatment effect to psychotherapeutic intervention. It is no news that psychotherapy has direct neural effects; we have known this for some time now, and as time passes, the field is growing ever more sophisticated in modeling the impact of psychotherapy on the brain. What was unique about this study was that in addition to reporting on positive treatment outcomes, this study illustrated the benefit of adding neural measures to symptom severity in the prediction of treatment response. This has important implications for future clinical trials, particularly if predictions for treatment response can be derived from combining subjective report of symptom improvement with an objective biological measure of brain functioning. This leads us to wonder whether we will ever be better off determining the benefits of an intervention by assessing clinical symptom severity alone.

Neural Correlates of Weight Gain With Olanzapine

Mathews J, Newcomer JW, Mathews JR, et al
Arch Gen Psychiatry. 2012;69(12):1226-1237.

Objectives: Iatrogenic obesity caused by atypical antipsychotics increases the rate of death from all causes. Olanzapine is a commonly prescribed atypical antipsychotic medication that frequently causes weight gain. To our knowledge, the neural correlates of this weight gain have not been adequately studied in humans.  To test the hypothesis that olanzapine treatment disrupts the neural activity associated with the anticipation and receipt (consumption) of food rewards (chocolate milk and tomato juice).


  • Twenty-five healthy individuals were recruited in this study.
  • Event-related functional magnetic resonance imaging data was collected at a university neuroimaging center, before and after a 1-week treatment with olanzapine.
  • Changes in blood oxygen level–dependent activations to the anticipation and receipt of food rewards after olanzapine treatment were the outcome measures.



Healthy Participants (N=25)

1 week follow-up after treatment with olanzapine

Significant increases in weight, food consumption, and disinhibited eating.

Imaging during anticipation of food reward

Enhanced activations in the inferior frontal cortex, striatum, and anterior cingulate cortex to the anticipation of a food reward.

Imaging during receipt of food reward

Activation in the caudate and putamen were enhanced to the receipt of the rewarding food.

Imaging during receipt of food reward

Decreased reward responsivity to receipt of the rewarding food in the lateral orbital frontal cortex, an area of the brain thought to exercise inhibitory control on feeding.

  Olanzapine treatment enhanced both the anticipatory and consummatory reward responses to food rewards in the brain reward circuitry that is known to respond to food rewards in healthy individuals. We also noted a decrease in responsivity to food consumption in a brain area thought to inhibit feeding behavior.

Clinical Commentary
This study examines the neural effects of an adverse side effect associated with pharmacological treatment. Olanzapine is well known to cause weight gain but the neural mechanisms associated with this common side effect are largely unknown. Previously healthy individuals were administered olanzapine for one week to assess neural responses to processing food rewards. After 1 week of olanzapine treatment, healthy individuals had significant increases in weight, food consumption, and disinhibited eating. Corresponding to this behavior, this study found enhanced anticipatory and consummatory reward responses to food reward in regions well known to be part of the brain’s reward circuitry and decreased responsivity to food consumption in brain regions that exert inhibitory control over feeding behavior. This study provides important insights about risks associated with use of psychotropic medications, and provides a clear neural mechanism to explain the increase in food consumption associated with this atypical antipsychotic. It would be interesting to see if neural outcome measures could be used in comparative effectiveness studies to compare various psychotropic medications on their propensity for weight gain, sedation, and other adverse events.  It would also be informative to see if a number needed to harm could be derived from neural outcome measures.


Improvement of Brain Reward Abnormalities by Antipsychotic Monotherapy in Schizophrenia

Nielsen MO, Rostrup E, Wulff S, et al
Arch Gen Psychiatry. 2012;69(12):1195-1204. 

Objectives: Schizophrenic symptoms are linked to a dysfunction of dopamine neurotransmission and the brain reward system. However, it remains unclear whether antipsychotic treatment, which blocks dopamine transmission, improves, alters, or even worsens the reward-related abnormalities. This study aimed to investigate changes in reward-related brain activations in schizophrenia before and after antipsychotic monotherapy with a dopamine D2/D3 antagonist.


  • Longitudinal cohort study occurred in psychiatric inpatients and outpatients in the Capital Region of Denmark.
  • Twenty-three antipsychotic-naive patients with first-episode schizophrenia and 24 healthy controls initially matched on age, sex, and parental socioeconomic status were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task.
  • Patients were treated for 6 weeks with the antipsychotic compound amisulpride. Controls were followed up without treatment.
  • Task-related blood oxygen level–dependent activations were measured by functional magnetic resonance imaging before and after antipsychotic treatment.



Subjects with First-episode Schizophrenia (N=23)

Healthy Comparison Participants (N=24)

Baseline imaging

Compared with controls, attenuation of brain activation during reward anticipation in the ventral striatum, bilaterally

Increase in ventral striatum activation during reward anticipation

Longitudinal follow-up

Among the patients, there was a correlation between the improvement of positive symptoms and normalization of reward-related activation


6-week follow-up after treatment with amisulpride (vs placebo)

Increases in the anticipation-related functional magnetic resonance imaging signal



Were no longer statistically distinguishable from healthy controls



Those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment.


To our knowledge, this is the first controlled, longitudinal study of reward disturbances in schizophrenic patients before and after their first antipsychotic treatment. Our results demonstrate that alterations in reward processing are fundamental to the illness and are seen prior to any treatment. Antipsychotic treatment tends to normalize the response of the reward system; this was especially seen in the patients with the most pronounced treatment effect on the positive symptoms.

Trial Registration Identifier: NCT01154829.

Clinical Commentary
This study is the first controlled longitudinal study examining reward disturbances in individuals with schizophrenia before and after their first antipsychotic treatment. Antipsychotic-naïve first-episode schizophrenia patients were scanned at baseline and then treated with the antipsychotic amisulpride for 6 weeks. A healthy comparison group matched on age, sex, and parental socioeconomic status were also examined with functional magnetic resonance imaging while playing a variant of a common reward-processing task called the monetary incentive delay task. At baseline, individuals with schizophrenia showed a blunted response in the ventral striatum, a hub region for reward processing. Remarkably, after 6 weeks of treatment, patients with schizophrenia showed an increase in the anticipation-related functional magnetic resonance imaging signal and were no longer statistically distinguishable from healthy controls. Improvement of positive symptoms in the schizophrenia group correlated with normalization of reward-related activation, and those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment. This study demonstrates the very specific way in which treatment with an antipsychotic can ameliorate illness-related deficits in reward processing. This provides insights about the pathophysiology of schizophrenia as well as a mechanism for treatment response. 


MR Imaging of the Effects of Methylphenidate on Brain Structure and Function in Attention-Deficit/Hyperactivity Disorder

Schweren LJ, de Zeeuw P, Durston S
Eur Neuropsychopharmacol. 2012 Nov 17.

Objective: Methylphenidate is the first-choice pharmacological intervention for the treatment of attention-deficit/hyperactivity disorder (ADHD). The pharmacological and behavioral effects of methylphenidate are well described, but less is known about neurochemical brain changes induced by methylphenidate. This level of analysis may be informative on how the behavioral effects of methylphenidate are established.

Methods: This paper reviews structural and functional MRI studies that have investigated effects of methylphenidate in children with ADHD.

Results: Structural MRI studies provide evidence that long-term stimulant treatment may normalize structural brain changes found in the white matter, the anterior cingulate cortex, the thalamus, and the cerebellum in ADHD. Moreover, preliminary evidence suggests that methylphenidate treatment may normalize the trajectory of cortical development in ADHD. Functional MRI has provided evidence that methylphenidate administration has acute effects on brain functioning, and even suggests that methylphenidate may normalize brain activation patterns as well as functional connectivity in children with ADHD during cognitive control, attention, and during rest.

Conclusions: The effects of methylphenidate on the developing brain appear highly specific and dependent on numerous factors, including biological factors such as genetic predispositions, subject-related factors such as age and symptom severity, and task-related factors such as task difficulty. Future studies on structural and functional brain changes in ADHD may benefit from inclusion strategies guided by current medication status and medication history. Further studies on the effects of methylphenidate treatment on structural and functional MRI parameters are needed to address unresolved issues of the long-term effects of treatment, as well as the mechanism through which medication-induced brain changes bring about clinical improvement.

Clinical Commentary
In an era of increasing use of psychostimulants both for the treatment of attention deficit with hyperactivity (ADHD) and cognitive enhancement, it is important to understand the neural effects of stimulant treatment, particularly in the developing brain. This paper reviews the structural and functional MRI studies that have investigated effects of methylphenidate in children with ADHD. Structural MRI studies suggest that long-term stimulant treatment can normalize ADHD-related structural anomalies found in the white matter, the anterior cingulate cortex, the thalamus, and the cerebellum. Moreover, methylphenidate treatment may normalize the trajectory of cortical development in ADHD over time. Functional MRI studies suggest that methylphenidate acutely affects brain function, normalizing brain activation patterns as well as functional connectivity in children with ADHD during cognitive control, attention, and during rest. These appear to be specific effects on the developing brain. However, it is important that treatment effects may be strongly dependent on biological factors such as genetic predispositions, subject-related factors such as age and symptom severity, and task-related factors such as task difficulty. These factors make it nearly impossible to infer a direct or causal neural mechanism of an intervention, especially in the context of a dynamic system such as the developing brain. However, it is reassuring to see several lines of evidence converge on a model for how methylphenidate exerts its beneficial effects on an inattentive brain. Future studies that address the potential confounds in the design of the study may provide more conclusive evidence about the effects of stimulants on the brain.



GME Research Review

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.

ISSUE 11, February 2013 — Guest Commentator: Ashwin A. Patkar, MD, MRCPsych, Duke University Medical Center, Durham, NC

Randomized Trial of Long-Acting Sustained-Release Naltrexone Implant vs Oral Naltrexone or Placebo for Preventing Relapse to Opioid Dependence

Krupitsky E, Zvartau E, Blokhina E, et al.

Arch Gen Psychiatry. 2012;69(9):973-981.

Objective: Sustained-release naltrexone implants may improve outcomes of nonagonist treatment of opioid addiction. This study compared outcomes of naltrexone implants, oral naltrexone hydrochloride, and nonmedication treatment.

Methods: Six-month double-blind, double-dummy, randomized trial conducted in addiction treatment programs in St Petersburg, Russia. Participants included 306 opioid-addicted patients recently undergoing detoxification. Biweekly counseling and 1 of the following 3 treatments were given for 24 weeks: 1,000 mg naltrexone implant and oral placebo (NI+OP group; 102 patients); placebo implant and 50 mg oral naltrexone hydrochloride (PI+ON group; 102 patients); or placebo implant and oral placebo (PI+OP group; 102 patients). Percentage of patients retained in treatment without relapse was utilized as the main outcome measure.

Results: By month 6, 54 of 102 patients in the NI+OP group (52.9%) remained in treatment without relapse compared with 16 of 102 patients in the PI+ON group (15.7%) (survival analysis, log-rank test, P<.001) and 11 of 102 patients in the PI+OP group (10.8%) (P<.001). The PI+ON vs PI+OP comparison showed a nonsignificant trend favoring the PI+ON group (P=.07). Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P<.001, Fisher exact test, compared with the NI+OP group). Twelve wound infections occurred among 244 implantations (4.9%) in the NI+OP group, 2 among 181 (1.1%) in the PI+ON group, and 1 among 148 (0.7%) in the PI+OP group (P=.02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy. Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P=.12), and all resolved with anti-allergy medication treatment. Other non local-site adverse effects were reported in 8 of 886 visits (0.9%) in the NI+OP group, 4 of 522 visits (0.8%) in the PI+ON group, and 3 of 394 visits (0.8%) in the PI+ON group; all resolved and none were serious. No evidence of increased deaths from overdose after naltrexone treatment ended was found.

Conclusions: The implant is more effective than oral naltrexone or placebo. More patients in the NI+OP than in the other groups develop wound infections or local irritation, but none are serious and all resolve with treatment.

Clinical Commentary
Naltrexone is a mu-opioid antagonist that reduces the positive reinforcing effects of opioids and is approved to treat opioid dependence in the U.S. and several countries. Unfortunately, adherence to oral naltrexone is poor and clinical use has been limited except in selected groups of motivated patients. This study was done in Russia, where use of prescription opioid agonists (eg, methadone) to treat opioid addiction is highly restricted. The results showed that a 1,000 mg subcutaneous biodegradable 2-month naltrexone implant was superior to placebo implant and oral naltrexone on the primary outcome measure of retention without relapse. The outcome differences were striking. Over the 6-month study period, approximately 53% of patients in the naltrexone implant group remained in treatment without relapse compared to 16% in the oral naltrexone and 11% in the placebo group. All participants received biweekly drug counseling. Those with an active implant had a higher rate of wound infections (~5%) compared to the placebo implant group (~1%), but the infections were minor and successfully treated with oral antibiotics. The clinical considerations worth noting are: (1) Delivery systems that ensure sustained administration of naltrexone are effective to treat opioid dependence when combined with counseling; (2) Compliance with oral naltrexone limits its clinical utility; (3) Given the potential for diversion, misuse, and overdose of opioid agonists, naltrexone, a non-abusable and effective drug, deserves attention. Although naltrexone implant is not available in the U.S., an extended release, once monthly formulation of naltrexone is FDA approved. Commercial considerations are likely to influence future availability of the implant in the US.


Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive 'Bath Salts' Products

Baumann MH, Partilla JS, Lehner Kr, et al

Neuropsychopharmacology. 2012;Oct 17. doi: 10.1038/npp.2012.204. [Epub ahead of print]

Objective: The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods.

Methods: In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats.

Results: We found that MDPV blocks uptake of [(3)H]dopamine (IC(50)=4.1 nM) and [(3)H]norepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of [(3)H]serotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats.

Conclusions: Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.

Clinical Commentary

MDPV is the primary ingredient in "bath salts," synthetic designer drugs that are labeled as such to avoid criminal prosecution. Bath salts have seen a tremendous increase in popularity in recent years as drugs of abuse and have only been classified recently as controlled substances in the United States and some other countries. Intoxications with bath salts can have serious adverse effects, including acute psychosis with delusions, hallucinations, and bizarre behavior such as self-mutilation and violence. Physical effects can include hypertension, arrhythmias, and seizures. There has been limited information on mechanism of action of MDPV and its addictive potential. This preclinical study clearly demonstrates that MDPV is more selective and potent than cocaine in inhibiting the monoamine uptake leading to acute increase in dopaminergic transmission. This mechanism can explain the reinforcing nature of bath salt use, and the potentially dangerous physical and psychiatric manifestations of toxicity. It is worth noting that MDPV was 10 times more potent than cocaine in producing adverse cardiovascular effects in this study. Intoxication with bath salts should be a differential diagnosis in acute psychotic episodes, especially in young adults or adolescents who have a history of substance abuse. MDPV is not detected by routine drug screens but overdose can be life-threatening. Hence, clinicians must be especially vigilant about assessment of bath salt use.


A Double-Blind Randomized Controlled Trial of N-acetylcysteine in Cannabis-Dependent Adolescents

Gray KM, Carpenter MJ, Baker NL, et al

Am J Psychiatry. 2012;169(8):805-812.

Objective: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy.

Methods: In an 8-week, double-blind, randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1,200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group.

Results: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4; 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events.

Conclusions: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

Clinical Commentary

Cannabis is the most commonly used illicit drug among adolescents. Heavy use of cannabis has been associated with a variety of adverse effects. Existing behavioral treatments are associated with modest abstinence rates in adolescents. Furthermore, there is no medication that has demonstrated consistent efficacy in cannabis dependence. N-acetylcysteine (NAC) is an inexpensive, over-the-counter supplement that has been shown to upregulate the cysteine-glutamate exchanger and modulate glutaminergic neurotransmission. NAC also has anti-inflammatory properties that are linked to oxidative pathways. This is the first randomized controlled pharmacotherapy trial for cannabis dependence that showed a positive primary abstinence outcome as opposed to decreased use of cannabis in adolescents. About 41% of the NAC group were abstinent during the study compared to 27% of placebo-treated subjects.
At the dose employed (2.4 g per day), NAC did not have any significant side effects. While it is tempting to think of NAC as a daily supplement for cannabis dependence, more information is required. In this single-site study, NAC was effective when added to contingency management and brief cessation counseling. Will it be as effective in the absence of adjunctive psychosocial treatments? Are the effects of NAC sustained beyond the post-treatment period? Will it work for patients with dependence on other substances or high levels of psychopathology? It is hoped that we may have these answers in the near future. A large, federally funded, multi-site controlled trial of NAC for marijuana dependence in adolescents is underway.

Integrated Exposure-Based Therapy for Co-occurring Posttraumatic Stress Disorder and Substance Dependence: A Randomized Controlled Trial

Mills KL, Teesson M, Back SE, et al

JAMA. 2012;308(7):690-699.

Objective: There is concern that exposure therapy, an evidence-based cognitive-behavioral treatment for posttraumatic stress disorder (PTSD), may be inappropriate because of risk of relapse for patients with co-occurring substance dependence. This study aimed to determine whether an integrated treatment for PTSD and substance dependence, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), can achieve greater reductions in PTSD and substance dependence symptom severity compared with usual treatment for substance dependence.

Methods: Randomized controlled trial enrolling 103 participants who met DSM-IV-TR criteria for both PTSD and substance dependence. Participants were recruited from 2007-2009 in Sydney, Australia; outcomes were assessed at 9 months post baseline, with interim measures collected at 6 weeks and 3 months post baseline. Participants were randomized to receive COPE plus usual treatment (n=55) or usual treatment alone (control) (n=48). COPE consists of 13 individual 90-minute sessions (ie, 19.5 hours) with a clinical psychologist. The main outcome measures were change in PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS; scale range, 0-240) and change in severity of substance dependence as measured by the number of dependence criteria met according to the Composite International Diagnostic Interview version 3.0 (CIDI; range, 0-7), from baseline to 9-month follow-up. A change of 15 points on the CAPS scale and 1 dependence criterion on the CIDI were considered clinically significant.

Results: From baseline to 9-month follow-up, significant reductions in PTSD symptom severity were found for both the treatment group (mean difference, -38.24 [95% CI, -47.93 to -28.54]) and the control group (mean difference, -22.14 [95% CI, -30.33 to -13.95]); however, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity (mean difference, -16.09 [95% CI, -29.00 to -3.19]). No significant between-group difference was found in relation to improvement in severity of substance dependence (0.43 vs 0.52; incidence rate ratio, 0.85 [95% CI, 0.60 to 1.21), nor were there any significant between-group differences in relation to changes in substance use, depression, or anxiety.

Conclusion: Among patients with PTSD and substance dependence, the combined use of COPE plus usual treatment, compared with usual treatment alone, resulted in improvement in PTSD symptom severity without an increase in severity of substance dependence.

Clinical Commentary

Exposure therapy, a cognitive-behavioral therapy involving exposure to memories and reminders of past trauma, has long been regarded as a gold standard treatment for PTSD. However, there has been a concern that exposure therapy may be inappropriate for patients with co-occurring substance dependence because it may activate unpleasant memories and trigger relapse. To date, there was an absence of evidence to support or refute this belief because most trials of PTSD treatment have excluded individuals with substance dependence. Mills and colleagues from Australia have published the first large, randomized controlled trial of an integrated treatment for PTSD and substance dependence that incorporated prolonged exposure therapy. The researchers found that from the beginning of the study to 9-month follow-up, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity compared with the control group. By 9 months, rates of substance dependence had decreased to 45.4% in the treatment group and 56.2% in the control group; however, the difference between groups was not statistically significant. There are two important take-home messages from the study. First, most patients continued to use substances throughout the study. This indicates that abstinence from substances is not required for exposure therapy to be effective for PTSD in patients with comorbid substance abuse. Second, it is important to integrate exposure therapy with evidence-based treatments for substance dependence because no significant benefits were observed for substance-related outcomes with exposure therapy. We await replication of these results in a US sample, especially in those with combat trauma.


Randomized Controlled Trial of Contingency Management for Stimulant Use in Community Mental Health Patients With Serious Mental Illness

McDonell MG, Srebnik D, Angelo F, et al

Am J Psychiatry. 2012 Nov 9. doi: 10.1176/appi.ajp.2012.11121831. [Epub ahead of print]

Objective: The primary objective of this study was to determine whether contingency management was associated with increased abstinence from stimulant drug use in stimulant-dependent patients with serious mental illness treated in a community mental health center. Secondary objectives were to determine whether contingency management was associated with reductions in use of other substances, psychiatric symptoms, HIV risk behavior, and inpatient service utilization.

Methods: A randomized controlled design was used to compare outcomes of 176 outpatients with serious mental illness and stimulant dependence. Participants were randomly assigned to receive 3 months of contingency management for stimulant abstinence plus treatment as usual or treatment as usual with reinforcement for study participation only. Urine drug tests and self-report, clinician-report, and service utilization outcomes were assessed during the 3-month treatment period and the 3-month follow-up period.

Results: Although participants in the contingency management condition were significantly less likely to complete the treatment period than those assigned to the control condition (42% compared with 65%), they were 2.4 times (95% CI=1.9-3.0) more likely to submit a stimulant-negative urine test during treatment. Compared with participants in the control condition, they had significantly lower levels of alcohol use, injection drug use, and psychiatric symptoms and were one-fifth as likely as those assigned to the control condition to be admitted for psychiatric hospitalization during treatment. They also reported significantly fewer days of stimulant drug use during the 3-month follow-up.

Conclusions: When added to treatment as usual, contingency management is associated with large reductions in stimulant, injection drug, and alcohol use. Reductions in psychiatric symptoms and hospitalizations are important secondary benefits.

Clinical Commentary

About 50% of patients with serious mental illness suffer from a substance use disorder at some point in their lives. Contingency management is an evidence-based intervention for substance dependence in which individuals are provided with reinforcers (eg, vouchers, prizes) based on abstinence from drugs. The present study is the first adequately powered randomized controlled trial conducted to evaluate the efficacy of 12-week, contingency management alone or as an adjunct to treatment as usual for cocaine and/or methamphetamine dependence in 176 patients with schizophrenia, bipolar disorder, or recurrent major depressive disorder. The results were impressive. Participants who received the contingency management intervention showed favorable effects on stimulant-negative urine samples during treatment (primary outcome) as well as several secondary outcomes such as alcohol use, HIV risk behavior, psychiatric symptoms, and inpatient care (138 fewer days of hospitalization in treatment group versus control group). Of note, the positive effects of contingency management on stimulant abstinence persisted after treatment was discontinued. The intervention was delivered at low cost. For example, the cost of urine testing and reinforcers was $256 per participant for the treatment group. The principal limitation was that 42% of subjects completed contingency management compared to 65% in the control group, suggesting that acceptability of the intervention among patients with serious mental illness is not universal. Unfortunately, despite empirical support and potential cost savings, it appears that contingency management will continue to be underutilized in clinical settings until payers provide funding for the costs of delivering this treatment.

The Role of the Asn40Asp Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review

Ray LA, Barr CS, Blendy JA, et al

Alcohol Clin Exp Res. 2012;36(3):385-394.

The endogenous opioid system has been implicated in the pathophysiology of alcoholism, as it modulates the neurobehavioral effects of alcohol. A variant in the mu-opioid receptor gene (OPRM1), the Asn40Asp polymorphism has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: genetic association studies; behavioral studies of alcoholism; neuroimaging studies; pharmacogenetic studies and clinical trials; and preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response.

Clinical Commentary

The research enthusiasm for advancing our understanding of the genetic underpinnings of alcohol dependence has yet to be translated into clinical benefit. There is convergence of evidence that the mu-opioid receptor gene (OPRM1) may be a promising candidate gene in alcohol dependence. This review focuses on effects of the allelic variations in the OPRM1 gene, the Asn40Asp polymorphism in particular, on the etiopathology and treatment of alcohol dependence. Clinicians and researchers should take note of the rapidly accumulating evidence for the effect of the ORM1 Asn40Asp polymorphism on alcohol-related endophenotypes and response to opioid antagonist medications. Post hoc analyses of the COMBINE study, one of the largest controlled trial in alcohol dependence, showed that this polymorphism predicted response to naltrexone, an FDA-approved medication for alcohol dependence. If these findings are confirmed by a prospective randomized controlled pharmacogenetic clinical trial, it opens up the possibility for the OPRM1 receptor to be examined as a genetic biomarker for alcohol dependence and moreover for the FDA to consider pharmacogenetic indications in alcohol dependence. Although much work remains to be done, it appears that this line of research holds promise for increased understanding of pathways to risk and recovery from alcohol dependence and improving treatment outcomes.


To contact GME, email us at [email protected]

GME does not provide medical advice. The website and articles are intended for informational purposes only. They are not a substitute for professional medical advice, diagnosis or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on the GME Website. If you think you may have a medical emergency, immediately call your doctor or dial 911.

Log In

Join GME For Free

Become a GME subscriber and gain full access to our extensive library of 700+ psychiatric medical education videos, free CME webcasts, latest research updates, and more. To sample our content, watch the featured videos below.
Join Today!