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Issue 46, Feb 2016
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What is and what is not a good combination for bipolar depression

Geddes et al.; CEQUEL Investigators and Collaborators. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2015 Dec 10. pii: S2215-0366(15)00450-2. [Epub ahead of print] PubMed PMID: 26687300.

Major depressive episodes associated with bipolar disorders (“bipolar depression”) are notoriously difficult to treat.


Therefore, combination treatment is frequently used, but relatively little data is available as to their use in bipolar depression.



The British investigators who had led a previous important study (the BALANCE study) of the combination of lithium and valproate, have now conducted and published another important clinical trial of combination treatment for bipolar disorder.



The study aimed to determine whether combination therapy with quetiapine plus lamotrigine in persons with bipolar depression leads to greater improvement in depressive symptoms over 12 weeks than quetiapine monotherapy.


This was a double-blind, randomized, placebo-controlled, clinical trial conducted at multiple sites in the United Kingdom.


It is known by the acronym CEQUEL.


Persons with either bipolar I disorder or bipolar II disorder who required new treatment for a depressive episode were enrolled.


All participants received quetiapine in a flexible dose -- aimed at 300 mg/day, but at least 150 mg/day.


Patients were randomly assigned to treatment with either lamotrigine (n=101) or placebo (n=101). Lamotrigine was titrated up to 200 mg/day. The dose was altered if the person was on other medications that would affect levels of lamotrigine.


They were also, separately, randomly assigned to treatment with folic acid (500 mcg/day) or placebo.


A type of study design called a 2 × 2 factorial randomized clinical trial was used. What this means is that participants were divided into four groups as follows (with all four groups receiving quetiapine as well):


Lamotrigine + Placebo

Placebo + Placebo

Lamotrigine+ Folic acid

Folic acid+ Placebo



What this design does is to allow the investigators to assess the effect of lamotrigine alone, folic acid alone, and of the combination of lamotrigine and folic acid.


After 12 weeks of treatment, persons who received lamotrigine plus quetiapine had lower severity of depression (a difference of 1.7 points on the QIDS-SR), but the difference was not statistically significantly different, i.e., could have occurred by chance alone. The p value was close to significant (p=0.066), but it is a slippery slope to start considering close to statistically significant as being statistically significant.


But the authors also looked at the same question in another way as well. After 12 weeks of treatment, is lamotrigine plus quetiapine more efficacious than quetiapine alone? At 12 weeks, the percentage of persons meeting criteria for remission from depression was statistically significantly greater for those receiving lamotrigine (31%) versus those receiving placebo (16%). Keeping in mind a rule of thumb that a 10% or greater difference in an outcome is usually clinically significant, the benefit from adding lamotrigine to quetiapine was an important one.


At 52 weeks, persons who received lamotrigine had statistically significantly lower severity of depression than those who received placebo.


Persons who received folic acid did not benefit more than those who received placebo.


Even though this was the not the main purpose of doing the study, a surprising and intriguing finding in the study was the following: After 12 weeks of treatment, persons who received folic acid along with the lamotrigine had worse outcomes than those who received lamotrigine alone. The reason for this is not clear.



Given that folic acid seemed to interfere with the benefit of lamotrigine, the investigators looked at the benefit in the lamotrigine alone group at 12 weeks. This time, the benefit was clearly statistically significant.


Addition of lamotrigine to quetiapine improved the severity of depression more than quetiapine alone.



Folic acid seems to counteract the beneficial effect of lamotrigine.

Clinical Commentary

Combination treatment with mood stabilizers is very commonly used, so more research on this is definitely welcome.


While looking at any study of lamotrigine, I think it is more important to look at longer-term outcomes than short-term outcomes. Why? Because the onset of benefit from lamotrigine takes a longer time than other medications since it has to be titrated up.


While lamotrigine may be a good choice in the long run for many persons with bipolar disorder, there is a need to combine it with another medication that may have a more rapid onset of effect. Thus, the combination of quetiapine and lamotrigine is appealing. In clinical practice, the quetiapine could be tapered off later.



Vitamins and other supplements are not harmless. Lamotrigine is believed to interfere with the metabolism of folic acid, but now it seems like folic acid may also interfere with the effect of lamotrigine in bipolar depression. Pending further investigation, we should advise our patients with bipolar disorder to not take lamotrigine and folic acid together.

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Does antidepressant use in pregnancy increase risk of autistic spectrum disorder? Study 1


Boukhris et al. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatr. 2015 Dec 14:1-8. PubMed PMID: 26660917.

This study understandably received a lot of press.


There is some previous data suggesting that antidepressant use by mothers increases risk of autistic spectrum disorder in their babies. If this is true, pregnant women should be told about this increased risk given the potential seriousness of the problem.  


But, the association between the use of antidepressants during pregnancy and the risk of autism spectrum disorder in children born from those pregnancies is still controversial.



This study adds significantly to the literature on this question.


This study aimed to evaluate the association between antidepressant use during pregnancy and risk of autism spectrum disorder in children born from those pregnancies.



It aimed to evaluate this risk separately for each trimester during which the antidepressant was taken and to take into account presence or absence of depression in the mothers.


The study was based on data already available in a database.


It was part of an ongoing study of a large population of persons, called the Québec Pregnancy/Children Cohort. This group of individuals includes data on all pregnancies and children born in Québec, Canada, during a two-year period (2008 and 2009).


The sample included 145,456 infants born alive as singletons and at full-term.


Their mothers had to be covered by a specific insurance plan to pay for their medication for at least 12 months before and during the pregnancy (so that data on their antidepressant use could be obtained).


Children were considered to have autism spectrum disorder if they were diagnosed with autism spectrum disorder at least once between their birth and end of follow up.



Statistical adjustments were made for other factors that are known to be associated with autism spectrum disorder (i.e., potential confounders).



The children were followed up for a variable period with a mean of 6.2 years (standard deviation 3.2 years).


During this follow-up period, 0.7% of the children were diagnosed with autism spectrum disorder.


Four times more boys were diagnosed with autism spectrum disorder than girls.


Use of any antidepressant during the second and/or third trimester was associated with increased risk of autism spectrum disorder (31 of the exposed infants). The statistically adjusted hazard ratio was 1.9.


Use of selective serotonin reuptake inhibitors during the second and/or third trimester was associated with an increased risk of autism spectrum disorder (22 of the exposed infants). The statistically adjusted hazard ratio was 2.2.


On the other hand, there was no association between use of antidepressants in the first trimester and autism spectrum disorder in the child.


Could depression be the real, underlying reason why it appears that antidepressants increase risk of autism spectrum disorder in the children? This study tried to take that into account statistically, but the there was still an increased risk (adjusted hazard ratio, 1.8).


The authors point out the following facts that suggest that an association between maternal use of antidepressants and autism spectrum disorder in the child is not biologically implausible:

- Serotonin can affect processes like cell division, neuronal migration, cell differentiation, and synaptogenesis.


- Persons with autism spectrum disorder are known to tend to have elevated levels of serotonin in their platelets.


 Children with autism spectrum disorders tend to have abnormal development in the capacity of the brain to synthesize serotonin.



- Serotonin receptor 2A binding is altered in the cerebral cortex of persons with autism spectrum disorders.


Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of autism spectrum disorder in children born from those pregnancies.



This is true even after taking maternal depression into consideration.

Clinical Commentary

In my experience, the medical profession has leaned towards minimizing the risk of medication during the pregnancy. But over the years, increasing data has forced the profession to accept that there are some risks of taking an antidepressant during pregnancy. This has been best shown with regard to use of paroxetine during pregnancy and cardiac malformations in the newborn.


I suggest that we should keep an open mind and follow the data rather than any preconceived biases that we may have.



As in all observational studies, it is not possible to say why antidepressants may be associated with increased risk of autism spectrum disorder.

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Does antidepressant use in pregnancy increase risk of autistic spectrum disorder (or ADHD)? Study 2

Castro et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry. 2016 Jan 5;6:e708. PubMed PMID: 26731445.

Because of the uncertainty and controversy about whether or not antidepressant use by mothers during pregnancy increases risk of autism spectrum disorder in their children, independent exploration of this troubling question is needed.


The results of previous studies of this topic have been inconsistent.


The investigators combined electronic health data from multiple health systems.


They identified children with diagnoses of autism spectrum disorder or of attention deficit hyperactivity disorder and matched them with children without a diagnosis of any neurodevelopmental disorder.



They attempted to statistically control for sociodemographic and other factors that also increase risk of these disorders.


Children with a diagnosis of autism spectrum disorder (n=1245) or attention deficit hyperactivity disorder (n=1701) were identified.


A set of control children were identified who were matched on age, gender, and socioeconomic status to the children with the disorders.


Use of antidepressant medication during pregnancy was not associated with either autism spectrum disorder or attention deficit hyperactivity disorder.



On the other hand, use of an antidepressant by the mother prior to pregnancy was associated with an increased risk of both autism spectrum disorder and attention deficit hyperactivity disorder.


The author concluded that previous reports of association between prenatal use of antidepressant medication by mothers and diagnoses of autism spectrum disorder or attention deficit hyperactivity disorder in the children were probably false-positive findings.



The reason for the apparent association between the two may, in part, be due to the association between depressive disorders in mothers and risk of autism spectrum disorder and ADHD in their children.

Clinical Commentary

Taken together, these two recently published papers serve as a sort of Rorschach test for both mental health professionals and the general public. Those who want to believe that antidepressant medications are very problematic will believe the study by Mata et al., while those who are already convinced that antidepressants are safe during pregnancy will readily quote the study by Castro et al.



While further research is awaited, how about we say that we don’t know? It is probably best to let patients know that the safety of antidepressants during pregnancy has not been established, discuss the concerns that have been raised, and limit use of antidepressants during pregnancy due to individual patients in whom the potential benefits outweigh the potential risks.

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Bariatric surgery can have serious mental health consequences


Bhatti et al. Self-harm Emergencies After Bariatric Surgery: A Population-Based Cohort Study. JAMA Surg. 2015 Oct 7:1-7. PubMed PMID: 26444444.

The obesity epidemic continues – about 6% of the population in the US is morbidly obese. And bariatric surgery is being increasingly used to treat obesity.


The proportion of persons with mental disorder is high in persons who are morbidly obese and in those who undergo bariatric surgery. Therefore, psychiatric evaluation prior to bariatric surgery is routine.


It is unclear whether or not bariatric surgery has mental health benefits due to improved self-image.



This study draws attention to potential adverse mental health consequences after the surgery.


It is common for candidates for bariatric surgery to have a history of self-harm behaviors, including suicidal ideation and past suicide attempts.


But are these behaviors reduced or increased after surgery?


A previous systematic review of 30 studies suggested that suicide risk for patients undergoing bariatric surgery was 4 times higher than in the general population. It was also suggested previously that more suicides may occur after bariatric surgery.



This study aimed to specifically compare the risk of self-harm behaviors before and after bariatric surgery.


This was a population-based study, i.e, not done in just one or a few hospitals.


A cohort design was used, i.e, persons were identified and then followed up to determine the outcomes.


8815 adults who underwent bariatric surgery were included.


Data on all self-harm related emergency room visits in the province were accessed.


For each person, self-harm emergencies were compared in the 3 years prior to surgery and the 3 years after surgery.





Of the 8815 persons studied, 81% were women.


The type of bariatric surgery was a gastric bypass in almost all of them (98.5%).


Four types of self-harm behaviors were recorded: Intentional self-poisoning by medications (ICD-10 X61- 64), Intentional self-poisoning by and exposure to alcohol (X65), Intentional self-poisoning by toxic chemicals (X66-69), and Intentional self-harm by physical trauma (X70-84).


Self-harm emergencies occurred during follow-up in 111 patients. So, the percentage of persons who had a self-harm emergency was 1.3%, relatively low.


But, most importantly, self-harm emergencies increased after surgery (3.6 per 1000 patient-years) compared with before surgery (2.3 per 1000 patient-years).


The most common method used was an intentional overdose (73% of emergencies).


The self-harm emergencies were clinically significant:  54% required ambulance transport to a hospital, 93.0% were classified as urgent, and 54% led to a hospital admission.


93% of the events occurred in persons diagnosed as having a mental health disorder during the 5 years before the surgery.


The mechanisms for increased self-harm after bariatric surgery are not known. The authors speculated on the following possibilities:


1. Changes in alcohol metabolism after surgery may increase the likelihood of alcohol intoxication or alcohol-related disinhibition with impulsivity leading to self-harm after surgery.


2. Increased stress and anxiety in postoperative patients may lead to anxiolytic use or exacerbation of preexisting mental health conditions.



3. The eating behaviors that lead to morbid obesity may be considered to be addictive behaviors, and after surgery, these persons may substitute substance use for food.



The risk of self-harm emergencies increased after bariatric surgery.


It is important to evaluate patients for suicide risk during follow-up.



Mental health follow-up needs to be continued for relatively long periods after the surgery in some persons.

Clinical Commentary



I think it is not only self-harm risk but also coping in general that needs to be assessed in persons who receive bariatric surgery. The surgery does not solve their mental health issues. If we take away one of the person’s main coping mechanisms -- eating -- the person may turn to alcohol/drugs or, if no relief is found, to self-harm.

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Is one in five resident physicians currently suffering from major depression?


Mata et al. Prevalence of Depression and Depressive Symptoms Among Resident Physicians: A Systematic Review and Meta-analysis. JAMA. 2015 Dec 8;314(22):2373-83. PubMed PMID: 26647259.

Previous studies have suggested that resident physicians have relatively high rates of depressive symptoms.


Not only does this represent personal suffering, but depression in our residents has been shown to be related to poor-quality patient care and to more medical errors.


The problem of depressive symptoms in residents is important not only to the residents and their families, but to the entire profession.



The publication of this paper has shone a spotlight on this problem and is provoking some much-needed soul searching among those who are responsible for the training of resident physicians.



We already know from previous studies that resident physicians are at a higher risk of depressive disorders than the general population. But different studies provide quite different numbers as to how common this is.



This study aimed to combine data from all the studies to provide a better estimate of how common clinical depression or depressive symptoms are in resident physicians.


A systematic search of multiple databases was done to identify peer-reviewed studies on the prevalence of depression or depressive symptoms among resident physicians that were published between 1963 and 2015.


The studies used either a structured interview or validated questionnaire.


For quality control, information was extracted independently by two trained investigators.


The statistical approach of meta-analysis was used to combine data from all the studies.



Point or period prevalence of depression or depressive symptoms were determined.


This study included data from 31 cross-sectional studies (9447 individuals) and 23 longitudinal studies (8113 individuals).


Of these 54 studies, 3 used clinical interviews and 51 used self-report questionnaires.


The overall pooled prevalence of depression or depressive symptoms was 29%, but this differed between studies depending on the methodology.


When looking only at studies where the assessment used is believed to correlate well with a diagnosis of major depressive disorder, the prevalence of depression was 20%.


Over the years, the prevalence of depression in resident physicians has been increasing by an estimated 0.5% per year.


Seven of the studies involved collection of data over time. From these studies, it was determined that when residency training started, depressive symptoms went up by a median of 16%.


Do you think interns are overworked and, therefore, are more likely to have depressive symptoms? There was no difference between studies of only interns and of only later-year residents.



Do you think that surgical residency has longer hours and so surgical residents may have more depressive symptoms? There were no differences between studies that looked only at nonsurgical residents and those that included surgical residents as well.


The estimated prevalence of depression or depressive symptoms among resident physicians was 29%, but it may vary from 21% to 43% depending on how you define depressive symptoms/ depression.



Obviously, further research is needed to determine how to prevent and treat depression in resident physicians.

Clinical Commentary

This study cannot clearly answer the question, Why do resident physicians have depressive symptoms or clinical depression?  However, the increase in depressive symptoms on starting residency and the finding of similar symptoms across specialties and countries suggests that the stress of residency training is one important factor.


I discussed this study with several residency program directors. They pointed to erosion of teamwork leading to reduction in social support in the workplace; greater focus on data, labs, and EMR leading to reduced interaction with patients and staff; huge debt burdens; a greater sense of being unprepared than in the past; increased requirements for productivity; decreased autonomy; burdensome documentation; and so on.


But concerns were also raised about false positive diagnoses of clinical depression in persons who are often sleep deprived and are stressed by the difficulties of their work.


It is concerning that efforts in recent years to limit work hours and improve work conditions for resident physicians does not seem to have reduced the prevalence of depressive symptoms in them.



The field needs to study this problem more carefully and to markedly increase efforts to reduce stress in residents and to mitigate its effects.

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Rajnish Mago, MD
Associate Professor of Psychiatry, Thomas Jefferson University

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is Associate Professor of Psychiatry at Thomas Jefferson University and is author of "The Latest Antidepressants and Side Effects of Psychiatric Medications: Prevention, Assessment, and Management." Dr. Mago selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry.

We are always carefully evaluating which research papers to discuss in GME Research Review. Have you come across a research paper published in the last 6 months that you think is clinically relevant? If you would like to ask Dr. Mago to consider analyzing it, please email him the citation at: [email protected]

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.

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