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Issue 59, Mar 2017
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Who is more likely to have side effects on an antidepressant?

Shankman SA, Gorka SM, Katz AC, Klein DN, Markowitz JC, Arnow BA, Manber R, Rothbaum BO, Thase ME, Schatzberg AF, Keller MB, Trivedi MH, Kocsis JH. Side Effects to Antidepressant Treatment in Patients With Depression and Comorbid Panic Disorder. J Clin Psychiatry. 2017 Jan 3. [Epub ahead of print] PubMed PMID: 28068460.


Side effects of antidepressants are clinically important and have a huge effect on whether patients continue to take the antidepressant.

However, our ability to predict who is more likely to have side effects on an antidepressant is quite limited.

This study aimed to assess whether depressed patients with comorbid panic disorder were more likely to experience side effects than those without panic disorder.

It also assessed whether a greater burden of side effects in patients with both depression and panic disorder predicted a poorer outcome for these patients.

Lastly, the study also examined the relationship between reporting side effects attributed to an antidepressant and having comorbid social phobia or generalized anxiety disorder. This was done in order to see whether the increased risk of side effects was specific to comorbid panic disorder or present with any comorbid anxiety disorder.


About 800 chronically depressed persons who were treated with an antidepressant for 12 weeks were systematically assessed for symptoms that may be side effects.  


Patients with major depressive disorder who had a diagnosis of panic disorder at any point in their life were more likely to have gastrointestinal, cardiac, neurologic, and genitourinary side effects during treatment with an antidepressant. The odds ratios for having these side effects compared to those who did not have panic disorder ranged from 1.6 to 3.0.


However, there was no increase in reporting of other groups of symptoms (dermatological, eye/ear, sexual functioning).

What are the consequences of this increased perception of side effects? The increases in frequency, intensity, and impairment with side effects were more strongly associated with increases in depressive symptoms for persons with depression and comorbid panic disorder compared to those without comorbid panic disorder.

Are these effects present in all anxiety disorders or only with panic disorder? This is the first study to compare persons with major depression and comorbid panic disorder to those with other comorbid anxiety disorders. Neither comorbid social phobia nor comorbid generalized anxiety disorder were associated with increased risk of reporting side effects.


Persons with chronic depression who also have panic disorder are more likely to report side effects of antidepressants. 

These persons are also more likely to have worsening of depressive symptoms due to these side effects.

Clinical Commentary

This study confirms what we have kind of known all along—that persons with panic disorder (with or without major depressive disorder) are more likely to report “side effects” of medications.

I put “side effects” in quotes, because these were symptoms reported by patients and it is an assumption that they were side effects of the medication.

A hypothesis to explain these findings is that persons with panic disorder may be unusually aware of bodily sensations.

I find it interesting that this increased reporting of “side effects” was present in persons who had a lifetime comorbidity of panic disorder, not just current panic disorder.

When treating any person with panic disorder, we should always start the antidepressant at no more than half of the usual starting dose, perhaps even less.  

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Stimulants are not the only treatment for college students with ADHD

Gu Y, Xu G, Zhu Y. A Randomized Controlled Trial of Mindfulness-Based Cognitive Therapy for College Students With ADHD. J Atten Disord. 2016 Dec 1:1087054716686183. [Epub ahead of print] PubMed PMID: 28038496.


Between 2% and 8% of college students meet criteria for ADHD, but research into treatment of ADHD in this population has been very limited.

Clinicians feel uncomfortable about simply prescribing stimulants to college students with ADHD without recommending additional interventions.

This study evaluated the potential effectiveness of mindfulness-based cognitive therapy (MBCT) for the treatment of ADHD in college students.

Mindfulness-based cognitive therapy (MBCT) is a modification of Mindfulness-Based Stress Reduction that is used to treat clinical depression. The authors modified MBCT for treatment of ADHD.


Fifty-four undergraduate college students aged 19 to 24 years who had ADHD were enrolled.

The subjects were randomly allocated to either receive mindfulness-based cognitive therapy (MBCT) for six weeks or to be followed as wait-list controls.

The MBCT treatment provided was a modification of the standard MBCT protocol for treatment of clinical depression (Segal et al., 2002).

The MBCT treatment consisted of:

1. Six individual sessions, one per week, that lasted for one hour. Note: In contrast, MBCT for depression is provided in a group format.

2. Compact disks (CDs) were provided and participants were told to practice mindfulness with the help of these CDs for about 30 minutes daily.

3. Participants were asked to complete workbooks that incorporated education specific to ADHD.


Both groups were assessed prior to the intervention, after the intervention, and at a follow up visit three months after end of treatment. The person doing the assessment was blinded as to which group the participant was in.


Subjects who received mindfulness-based cognitive therapy (MBCT) had greater improvements in:

1. Mindfulness as measured by the Mindful Awareness and Attention Scale.

2. ADHD symptoms as measured with the Conners Adult ADHD Rating Scale—Self-report version (CAARS-S).

3. Some measures of neuropsychological performance on the computerized Attentional Network Test.

4. Anxiety as measured by the Beck Anxiety Inventory.


However, statistically significantly greater improvements were not found with regard to:

1. Depressive symptoms as measured by the Beck Depression Inventory - II.

2. Academic performance as measured by the participants’ Grade Point Average (GPA) before and after the intervention.



MBCT may be a useful intervention for college students with ADHD.  

Clinical Commentary

This was a relatively small study and was done in students who were in general psychology courses in China. I hope that more research is done on the usefulness of various mindfulness interventions in persons with ADHD.

However, it is encouraging that the treatment provided was relatively simple and brief (only six sessions). Thus, it could be implemented on a wide scale, especially if it was done in a group setting.


I recommend mindfulness medication (one component of the treatment provided in this clinical trial) to all my patients with adult ADHD.

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Do SSRIs increase the risk of preterm birth?

Eke AC, Saccone G, Berghella V. Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and risk of preterm birth: a systematic review and meta-analysis. BJOG. 2016 Nov;123(12):1900-1907. PubMed PMID: 27239775.


Depressive disorders are common during pregnancy.

Both depression and use of antidepressants have been associated with a variety of pregnancy complications including preterm births, low birth weight, fetal growth restriction, and postnatal complications.

This study aimed to summarize the research on the relationship between the use of

selective serotonin reuptake inhibitors (SSRIs) during pregnancy and preterm birth.


A very thorough search of the medical literature was done.

Studies were included if:

a) They reported the incidence of preterm birth after any exposure to SSRIs during pregnancy, and

b) They had a control group of pregnant women who had not taken an SSRI during pregnancy.

Both cohort and case-control studies were included.


The primary outcome was the incidence of preterm birth at less than 37 weeks.


Eight studies were included that had about 94,000 women in the exposure group (had taken an SSRI during pregnancy) and about 1.1 million women in the control group (had not taken an SSRI during pregnancy).

After adjusting for potential confounders, the incidence of preterm birth was statistically significantly higher in the group of women who had taken an SSRI during pregnancy compared to women who had not taken an SSRI during pregnancy. The odds ratio for this was 1.24.

Since taking an SSRI is related in part to being depressed, analyses were also done separately that compared depressed women who had taken an SSRI during pregnancy (preterm birth in 6.8%) to women who were depressed during pregnancy but had not taken an SSRI during pregnancy, i.e., had been treated with psychotherapy alone (preterm birth in 5.8%; odds ratio 1.17).


Women who received an SSRI during pregnancy had a statistically significantly higher risk of having a preterm birth compared with controls.

These women also had an increased risk compared to women who were depressed but had not taken an SSRI during pregnancy.

Clinical Commentary

Preterm birth is associated with a variety of problems, so this line of research is clinically important for informing pregnant women of the potential risks of taking an SSRI during pregnancy.

It is an important finding that of women who were depressed during pregnancy, those who received an SSRI were more likely to have a preterm birth than those who did not. In other words, women who were depressed during pregnancy but did not receive an SSRI did not have as much of a risk of preterm birth. This analysis is significant because it is often believed that the risks during pregnancy are due to the depression and not due to the antidepressant.

However, as acknowledged by the authors, this comparison does not completely rule out the possibility that the preterm birth was related to the depression rather than to the SSRI. Depressed women who take an SSRI are, in many cases, not the same as those treated with psychotherapy alone. Women who are more severely depressed are generally more likely to be prescribed and to take medication for depression. This meta-analysis was not able to statistically take the severity of depression into account.

Though not discussed here, there are often significant risks associated with not treating depression during pregnancy. The decision on whether or not to use antidepressants during pregnancy should, therefore, depend on a careful risk-benefit analysis for each woman.  

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Sitting is the new smoking

Stubbs B, Williams J, Gaughran F, Craig T. How sedentary are people with psychosis? A systematic review and meta-analysis. Schizophr Res. 2016 Mar;171(1-3):103-9. PubMed PMID: 26805414.


Prolonged sedentary behavior (spending too much time sitting or lying down despite being awake) is known to be independently associated with diabetes, cardiovascular disease, cancer, and premature death.


This meta-analysis combined data from all studies of how common sedentary behavior is in persons with psychosis.


Studies in persons with psychosis (schizophrenia spectrum or bipolar disorders) that looked at sedentary behavior with either a self-report questionnaire or an objective measure like an accelerometer were included.

A meta-analysis of the data from all these studies was done.  


Thirteen studies with a total of about 2000 participants were included.

The participants were 25 to 60 years old, about 2/3rds male, and had a BMI in the overweight or obese range.

Persons with psychosis spent about 11 hours per day being sedentary.

In studies in which objective measures were used, much higher levels of sedentary behavior were found (about 12 hours per day) than what participants had reported (about 7 hours per day).

Older age was also a predictor of increased sedentary behavior in these subjects.

Surprisingly, patients’ BMI did not significantly affect the extent of sedentary behavior (though, as noted, all the patients in this study were either overweight or obese).

Some studies compared persons with psychosis to controls. In these studies, the levels of sedentary behavior were, on an average, nearly 3 hours per day greater in persons with psychosis than in controls.  


Persons with psychosis engage in very high levels of sedentary behavior.

Self-report seems to significantly underestimate sedentary behavior.

Interventions specifically targeting sedentary behavior in this population should be studied.

Higher BMI should not be viewed as an obstacle to reducing sedentary behavior.  

Clinical Commentary

I think that sedentary behavior is a problem not only in persons with psychosis but also in persons with other mental disorders like major depressive disorder, etc.

While we should, of course, encourage our patients to exercise and counsel them about how to do so, we should also make a separate effort to reduce sedentary behavior. In addition to formally exercising, we can encourage our patients to not sit in one place for too long, to get up intermittingly while watching TV, to use the stairs whenever possible, and so on.

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Outpatient opioid detoxification with naltrexone or with buprenorphine?

Sullivan M, Bisaga A, Pavlicova M, Choi CJ, Mishlen K, Carpenter KM, Levin FR, Dakwar E, Mariani JJ, Nunes EV. Long-Acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid Detoxification With Naltrexone Versus Buprenorphine. Am J Psychiatry. 2017 Jan 10:appiajp201616050548. [Epub ahead of print] PubMed PMID: 28068780.


Naltrexone extended-release injection (brand name Vivitrol) is an important strategy for treating opioid dependence.

However, there is no agreement as to the best strategy for detoxifying these patients from opioids before starting them on naltrexone extended-release injection.

The commonly used approach is to detoxify patients by using a methadone or buprenorphine taper. But the problem with this approach is that in order to be started on naltrexone extended-release, the person has be free of opioids for 7 to 10 days. In that 7 to 10 day period, the person is not on either type of medication—an opioid agonist or some form of naltrexone. The person is, therefore, at substantial risk of relapse.

This study evaluated whether an alternative to this approach is feasible---giving an opioid (buprenorphine) for only one day and then starting the person on a low dose of oral naltrexone and gradually increasing the dose. This approach would allow patients to be started on naltrexone extended-release in only 7 days rather than the 14 days needed by the conventional approach of doing an opioid taper.


Opioid-dependent adults (n=150) were recruited and detoxified as outpatients.

They were randomly assigned to receive either naltrexone-assisted detoxification or buprenorphine-assisted detoxification.

1. Naltrexone-assisted detoxification was done over 7 days as follows: buprenorphine on day one, then oral naltrexone at gradually increasing doses. Clonidine and other adjunctive medications were given along with oral naltrexone.

2. Buprenorphine-assisted detoxification was also done over 7 days and involved giving buprenorphine and then gradually tapering off the dose. Then, no medication was given for a week before the naltrexone extended-release injection was given.


Participants from both groups received twice-weekly individual psychotherapy.

After the detoxification was over, an injection of naltrexone extended-release was given and then after 4 more weeks, a second dose of the injection was given.

The primary type, route, and amount of opioid use were taken into account in the statistical analyses.


Participants assigned to naltrexone-assisted detoxification were statistically significantly more likely to progress to receiving the naltrexone extended-release injection (56% versus 33%).

Similarly, participants assigned to naltrexone-assisted detoxification were statistically significantly more likely to receive the second injection of naltrexone extended-release at week 5 (50% versus 27%).

Surprisingly, during the first 7 days of treatment, the severity of withdrawal and discontinuation of treatment were not lesser in patients treated with a buprenorphine taper.

Not surprisingly, during the 7 days that patients in the buprenorphine-assisted detoxification group had to wait before naltrexone extended-release injection could be given, 29% of participants who completed the buprenorphine taper relapsed and, therefore, could not receive the naltrexone injection.

This study included persons who were dependent on either prescription opioids or heroin. The naltrexone-assisted detoxification followed immediately by administration of naltrexone extended-release injection was more efficacious in those dependent on prescription opioids than in heroin users.  


For outpatient detoxification, one day of buprenorphine followed by low-dose naltrexone (along with adjunctive non-opioid medications) worked well in terms of being able to start on naltrexone extended-release injections.

Clinical Commentary

The United States is in the midst of an opioid epidemic fueled to a great extent by abuse of prescription opioid medication.

Naltrexone-assisted detoxification should be considered as an alternative to the strategy most commonly used currently—tapering dose of an opioid—with which there are high rates of discontinuation of treatment and of relapse.

Adoption of naltrexone-assisted detoxification, especially in those dependent on prescription opioids may clinically significantly reduce relapse prior to being able to administer naltrexone extended-release.

However, this strategy may not be as suitable for those who were using substantial amounts of heroin and whose dependence on opioids is stronger.

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Rajnish Mago, MD
Medical Editor, GME Research Review

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who 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 come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Mago 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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