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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 30, September 2014: Guest Commentator—Michael Ostacher, MD, MPH, MMSc, Stanford University School of Medicine, Palo Alto, CA


Maintenance Treatment With Varenicline for Smoking Cessation in Patients With Schizophrenia and Bipolar Disorder: A Randomized Clinical Trial

Evins A, Cather C, Pratt SA, et al.
JAMA. 2014;311(2):145-154. doi:10.1001/jama.2013.285113.


Objective: It is estimated that more than half of those with serious mental illness smoke tobacco regularly. Standard courses of smoking cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy. Varenicline is also labeled as a drug that can worsen psychiatric conditions so is often not prescribed to patients with psychiatric disorders. The goal of this study is to determine whether smokers diagnosed with schizophrenia and bipolar disease are able to stay abstinent from tobacco longer with maintenance pharmacotherapy with varenicline than with standard treatment and whether the treatment is safe.



  • Outpatients with schizophrenia, schizoaffective disorder, or bipolar disorder between ages 18 and 70 who reported smoking 10 or more cigarettes per day for at least the prior year, had expired carbon monoxide levels greater than 9 ppm at screening.
  • Subjects were taking a stable clinically dose of antipsychotic (schizophrenia) or mood stabilizing (bipolar disorder) medication for 30 days or more before enrollment.
  • During an open-label phase, participants were given 0.5 mg of varenicline per day for 3 days, 0.5 mg twice a day for 4 days, then 1.0 mg twice a day for 11 weeks and were asked to attend 12 weekly, 1-hour, manualized group CBT sessions, then were asked to set a quit date between study weeks 4 and 5.
  • Participants in the open phase who were abstinence at weeks 11 and 12 were were randomized to the relapse prevention intervention: varenicline, 1.0 mg twice a day, or to placebo for weeks 12 through 52.
  • Participants received with a tapering schedule of relapse prevention–focused CBT groups during the maintenance phase. Sessions were held weekly for the first month (4 sessions), biweekly for 2 months (3 sessions), and monthly (8 sessions), for a total of 15 sessions over the 40-week relapse-prevention period.
  • The primary outcome was the 7-day point-prevalence abstinence rate at week 52. Secondary smoking-related outcomes were continuous abstinence rates during the randomized and follow-up phases, point-prevalence abstinence rates at week 64, and median time to first smoking relapse.
  • Point-prevalence abstinence at each visit was defined as self-reported smoking no cigarettes since the last visit and an expired carbon monoxide level of less than 9 ppm.


Results: 203 subjects met inclusion criteria and entered open-label treatment, 185 (91%) with schizophrenia and 18 (9%) with bipolar disorder. Eighty-seven of the 203 (43%) stopped smoking and had at least 14 days of continuous abstinence at the end of the 12-week open phase and were randomized to receive varenicline or identical placebo and a tapering schedule of CBT for weeks 12 through 52. Of those 87 subjects randomized, 77 (88.5%) had schizophrenia spectrum and 10 (11.5%) had bipolar disorder.


Twenty-four of 40 patients (60%) in the extended-duration varenicline group achieved biochemically verified, 7-day, point-prevalence abstinence at week 52 compared to 9 of 47 patients (19%) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2-19.2; P <.001). At week 76, 12 of 40 patients (30%) in the varenicline group compared to 5 of 47 (11%) in the placebo group had been continuously abstinent since randomizations at week 12 (for a total of 16 months) (OR, 3.4; 95% CI, 1.02-13.6; P = .03). Similar results were found for all planned outcomes measured.



There were 5 psychiatric hospitalizations among participants taking placebo and 2 among those taking varenicline, a non-significant difference.


Conclusion: Point-prevalence abstinence at 1 year was 3 times higher among those severely mentally ill participants assigned to maintenance varenicline treatment (60%) than among those assigned to placebo (19%).  Time to 50% relapse was only 35 days in the placebo group after varenicline was stopped despite weekly CBT during this period, indicating that weekly relapse-prevention focused CBT alone was not enough to maintain abstinence. Time to relapse was significantly longer in the varenicline group although approximately one-third of the varenicline group relapsed after CBT was tapered from weekly to monthly sessions during the maintenance period, suggesting that varenicline and CBT combined led to more sustained abstinence.


Clinical Commentary: Smoking is widely prevalent in those with severe mental illness and is a major factor in early mortality for these patients. This study answers two questions: whether varenicline is helpful in initiating smoking cessation in subjects with schizophrenia and bipolar disorder, and whether maintenance treatment with varenicline helps these subject stay quit when added to CBT for smoking cessation. The answer to both questions in this trial is yes. Varenicline was highly effective in leading to smoking cessation in the open-label phase of this study (43% quit by 12 weeks), and continued to be effective when used as a maintenance treatment, especially when combined with CBT.  This study strongly suggests that varenicline be offered to patients with severe mental illness, that varenicline should be continued for a year and beyond (rather than for the recommended 12 weeks), and that the benefits of treatment far outweigh the risks in patients willing to make an attempt at smoking cessation.


Varenicline for smoking cessation in bipolar disorder: a randomized, double-blind, placebo-controlled study

Chengappa KN, Perkins KA, Brar JS, et al.
 J Clin Psychiatry. 2014 Jul;75(7):765-772. PMID: 25006684


Objective: While varenicline has shown efficacy for smoking cessation, warnings about neuropsychiatric adverse events have been issued leading to concerns about its use in patients with psychiatric disorders, especially mood disorders. Since virtually no clinical trials for smoking cessation have been undertaken in bipolar disorder it is important that smoking cessation be studied in this population. This study assessed the efficacy and safety of varenicline in euthymic bipolar subjects who were motivated to attempt to stop smoking.



  • Clinically stable adult patients (aged 18-65) with DSM-IV bipolar disorder (n = 60).
  • Subjects had to smoke at least 10 cigarettes per day, CO levels > 10 ppm, be on no other smoking cessation pharmacotherapy for prior 3 months, and be willing to quit smoking within the next 30 days.
  • Subjects had to have MADRS and YMRS scores < 8, be on stable maintenance treatment for bipolar disorder for at least 8 weeks, and no psychiatric emergencies, violent or suicidal behavior, or psychiatric hospitalizations in the prior 6 months.
  • The study comprised a 1- to 2-weeks screening period, 12 weeks of treatment with varenicline or placebo, and 12 weeks of follow up.
  • Participants were given 0.5 mg of varenicline or matched placebo per day for 3 days, 0.5 mg twice a day for 4 days, then 1.0 mg twice a day for the remaining 11 weeks of the treatment phase of the study.
  • Subjects picked a target quit date after reaching full dose of study drug.
  • Primary outcome was the initiation of abstinence, defined as 7-day point prevalence of self-reported abstinence verified by CO levels < 10 ppm.
  • Changes in MADRS, YMRS, and CGI from baseline to end of study were analyzed using mixed-model ANOVA using general linear modes and included 3 time points: baseline, week 12, and week 24.


Results: Significantly more subjects quit smoking with varenicline (15 of 31, 48.4%) than with placebo (3 of 29, 10.3%) (OR = 8.1; 95% CI, 2.03-32.5; P < .002). At 24 weeks, 6 of 31 (19.4%) varenicline-treated subjects remained abstinent compared to 2 of 29 (6.9%) assigned to placebo, although this was non-significant (OR = 3.2; 95% CI, 0.60-17.6; P = .17). Psychopathology scores remained stable. Ten serious adverse events occurred (n = 6, varenicline; n = 4, placebo). Abnormal dreams occurred significantly more often in varenicline-treated subjects (18 of 31, 61.3%) than in those receiving placebo (9 of 29, 31%; Fisher exact test, P = .04). Eight varenicline-treated and 5 placebo-assigned subjects expressed fleeting suicidal ideation, which was not statistically significant.


Conclusion: In spite of a small sample size, this study found that varenicline is much more effective at leading to smoking cessation by 12 weeks than placebo, and that difference persists for 3 months after treatment ended. There was a high rate of relapse to smoking after treatment discontinuation in subjects receiving varenicline. There were no obvious differences in mood or other clinical outcomes.  The safety outcomes for both groups were similar, but small sample size does not allow conclusions to be drawn about the safety of varenicline in this population of subjects with bipolar disorder.


Clinical Commentary: Combined with the bipolar disorder subjects in the Evins study above, one can conclude that varenicline is an effective treatment for smoking cessation in patients with bipolar disorder, and that no large differences in clinical outcomes were found.  While not definitively answering the question of safety, it is certainly the case that varenicline is effective in reducing smoking in a population in dire need of help doing so.



Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study 

Diav-Citrin O, Shechtman S, Tahover E, et al. 
Am J Psychiatry
. 2014 Jul 1;171(7):785-94. doi: 10.1176/appi.ajp.2014.12111402.


Objective: Lithium is a mainstay of the treatment of bipolar disorder.  It has long been thought to have risks of teratogenicity, especially cardiac malformations, but no recent study has quantified the effects of the drug.  It is important to know what the risks are to women who are pregnant or planning to become pregnant who are treated with lithium so as to better inform them about the risks and benefits of using it during pregnancy.

This a prospective, comparative observational study to evaluate the risk of major anomalies following exposure to lithium during pregnancy.



  • Pregnant women who contacted the Israeli Teratology Information Service with regard to gestational exposure to lithium, between the years 1994 and 2010, were enrolled.
  • The lithium-exposed group was compared with the following two groups:
    • Pregnant women with bipolar disorder and no exposure to lithium who were counseled by the Israeli Teratology Information Service between the years 1999 and 2010 and who were untreated during pregnancy or treated with antipsychotics (e.g., haloperidol, risperidone) and/or antidepressants (e.g., duloxetine) or treated with mood stabilizers other than lithium, such as carbamazepine, valproic acid, lamotrigine, or topiramate
    • Pregnant women randomly selected from the Israeli Teratology Information Service database who were counseled during pregnancy between 1994 and 2010 with regard to exposures known not to be teratogenic at a 1:4 ratio.
    • Pregnancy outcome in the lithium-exposed group and the two comparison groups were collected after the expected date of delivery.
    • Follow-up was conducted by telephone interview to obtain details of pregnancy outcome, gestational age at delivery, birth weight, congenital anomalies, and neonatal complications.
    • Offspring were evaluated between the neonatal period and 7 years of age, but usually within the first 2 years of life.
    • Databases from Canada and Australia were used to increase the sample.
    • The primary outcome was the rate of major anomalies.
    • Secondary outcomes were the rates of live birth, miscarriage, pregnancy termination, stillbirth, ectopic pregnancy, preterm delivery (<37 completed weeks), gestational age at delivery, birth weight, and neonatal complications.


Results:  The overall rate of major congenital anomalies was not significantly different between the three groups. The analysis of major anomalies was repeated among those offspring exposed to lithium during the first trimester and after exclusion of genetic or cytogenetic anomalies, and no significant difference was found. However, cardiovascular anomalies were significantly more common in cases of lithium exposure during the first trimester when compared with the nonteratogenic group (χ2=12.1, df=1, p=0.005; crude relative risk=7.23, 95% CI [confidence interval]=1.97–26.53]), but there was no significant difference after excluding those anomalies that spontaneously resolved (relative risk=5.78, 95% CI=0.82–40.65). The rate of non-cardiovascular anomalies was not significantly different between the three groups.




Conclusion: The authors conclude in the abstract, “Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies. Women who are treated with lithium during organogenesis should undergo fetal echocardiography and level-2 ultrasound.”  Their results, however, do not necessarily support such a conclusion, as they as report, “The analysis of major anomalies was repeated among those offspring exposed to lithium during the first trimester and after exclusion of genetic or cytogenetic anomalies, and no significant difference was found. However, cardiovascular anomalies were significantly more common in cases of lithium exposure during the first trimester when compared with the nonteratogenic group but there was no significant difference after excluding those anomalies that spontaneously resolved. The rate of noncardiovascular anomalies was not significantly different between the three groups.”


Clinical Commentary: It is important to know whether or not lithium is associated with adverse birth outcomes, especially for women with bipolar disorder. Unfortunately, the results of this study do not answer the question definitively. While the authors conclude that lithium is associated with negative outcomes, the results of their study actually state that there are no differences in birth outcomes between lithium treated women, women treated with other potentially teratogenic drugs used in bipolar disorder, and women not exposed to teratogens.  The one outcome they find is a first-trimester cardiac abnormality that is no longer associated with lithium exposure when abnormalities that spontaneously resolve are included. There are reports of malformations in the lithium group that are numerically higher than in the other groups but which do not rise to the level of statistical significance.  It is impossible to know whether these risks would become statistically significant with larger samples, but they are difficult to ignore. 


Because of the risk of lithium discontinuation and the known risks for fetal malformations in other mood stabilizing treatment, women who are stable on lithium for bipolar I disorder (i.e. those with a past history of mania) may decide that continuation of lithium is a risk worth taking. For those women for whom it is unclear whether lithium is of significant benefit, careful consideration should be given to stopping lithium (and any drug that is not essential) even if the risk to the fetus is small.


Efficacy and Safety of Extended-Release Quetiapine Fumarate in Youth with Bipolar Depression: An 8 Week, Double-Blind, Placebo-Controlled Trial

Findling RL, Pathak S, Earley WR, et al. 
J Child Adolesc Psychopharmacol. 2014 Jun 23. [Epub ahead of print] doi:10.1089/cap.2013.0105.


Objective: Quetiapine is an approved treatment for pediatric bipolar mania and for schizophrenia in adolescents. It is approved as a monotherapy treatment for bipolar I & II depression in adults, but it is not known whether it is effective as a treatment for bipolar depression in children and adolescents.



  • This is an 8-week, double-blind, randomized, parallel-group, placebo-controlled study conducted at 42 centers in seven countries
  • Boys and girls 10–17 years of age with a DSM-IV-TR diagnosis of bipolar I or bipolar II disorder (current or most recent episode depressed and lasting at least 4 weeks), K-SADS-PL were included in the study
  • The study consisted of a screening and enrollment period of up to 35 days (including washout) followed by an 8-week double-blind treatment period with quetiapine XR or placebo, and a 1 week safety follow-up period.
  • The dose of quetiapine XR dose was from 150–300 mg/day, consistent with the dose investigated in adults with acute bipolar depression.
  • Stimulants for ADHD could be continued if the dose was stable for at least 30 days
  • The primary study outcome was the mean change in CDRS-R (a depression rating scale) total score from baseline to end-point in patients treated with quetiapine XR compared to placebo. CDRS-R scores were measured at screening and baseline and at weekly visits up to week 8.
  • Secondary study outcomes included response and remission rates. Response was defined as a ≥50% reduction from baseline in the CDRS-R total score and remission was defined as a CDRS-R total score ≤28 in patients who were assessed at week 8.
  • More subjects on quetiapine (n=7) developed clinically significant elevations in triglycerides compared to placebo (n=1), while 11 (12.5%) of the quetiapine XR and 6 (6.0%) of the placebo group experienced weight gain ≥7%.


Results: Of 262 patients enrolled in the study, 193 patients (n=93, quetiapine XR group; n=100, placebo group) were randomized to study treatment.  There was no difference between quetiapine and placebo on the primary outcome measure.  Least squares (LS) mean changes in CDRS-R total score were −29.6 (SE, 1.65) with quetiapine XR and −27.3 (SE, 1.60) with placebo, a between-treatment group difference of −2.29 (SE, 1.99; 95% CI, −6.22, 1.65; p=0.25; MMRM). For the secondary outcome measures there were no differences on response rates (≥50% reduction in adjusted CDRS-R total score from baseline to week 8, observed cases): 63.0% with quetiapine XR (n=58) and 55.0% with placebo (n=55) (odds ratio [OR] 1.20; p=0.63) or remission rates (CDRS-R score ≤28 at week 8, observed cases):v45.7% with quetiapine XR (n=42) and 34.0% with placebo (n=34) (OR, 1.60; p=0.16).


Conclusions: Quetiapine XR (150 to 300 mg/day) did not demonstrate efficacy relative to placebo in this large, 8 week, randomized study of youth with bipolar I or II depression. These findings are in contrast to those in adults. There was a high placebo response rate – both groups improved significantly – which may have hampered the ability of the study to detect a difference, if one actually exists, between quetiapine XR and placebo for bipolar depression.  Triglyceride increases and weight gain were higher in the quetiapine group than the placebo group.


Clinical Commentary: Quetiapine XR was not shown to be more effective as a treatment for bipolar depression in youth than placebo, and was associated with more weight gain and lipid elevations.  This is a disappointing finding in that there are few treatments for bipolar disorder in children and adolescents that have been validated in large, placebo-controlled, well-designed clinical trials.  The high placebo response rate may point to two things: that the instability of depression in adolescents makes it difficult to identify a population that would respond to somatic therapy in trials, and that treatment engagement itself may be an important and powerful factor in the treatment of mood symptoms in youth with bipolar disorder.


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