• Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007 Sep;164(9):1356-63. doi:” [Link]
• Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012 Jun;69(6):580-7. doi: 10.1001/archgenpsychiatry.2011.2048. Erratum in: Arch Gen Psychiatry.2013 Aug;70(8):881. PMID: 22309973; PMCID: PMC3367101. [Link]
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Rough Transcript:

Dr. Feder: For 16 years, since the FDA black box warning about suicidality with antidepressants, our community has been quoting data that downplays this concern. We were wrong. We were deceived. Antidepressants can be lifesaving, but there really is a duty to warn. In this episode, Doctors Martha Ignazewski and Glen Speilmans talk with us about what went on and how to talk about it with our families.

Welcome to The Carlat Psychiatry Podcast.

This is a special episode from the child psychiatry team. 

I’m Dr. Josh Feder, The Editor-in-Chief of The Carlat Child Psychiatry Report and co-author of The Child Medication Fact Book for Psychiatric Practice. 

Mara: And I’m Mara Goverman, a Licensed Clinical Social Worker in Southern California with a private practice. 

I’m also a regional director at Positive Development Institute.

Dr. Feder: So let’s get right into it. The sound we’re using from this episode is an interview I did with Dr. Martha Ignaszewski, staff psychiatrist at BC Children’s Hospital and a clinical instructor at the University of British Columbia, and Dr. Glen Spielmans, a professor of psychology at Metropolitan State University in Saint Paul, Minnesota. Glen started by giving us the background.

Dr. Spielmans: In 2004, the FDA required a black box warning for antidepressants, which said that antidepressants lead to a higher risk of suicidality than placebo among children and adolescents. The warning was updated in 2006 to include young adult patients (up to age 24). Shortly after that, some researchers reported that this warning had a bad outcome—namely, that it resulted in fewer antidepressant prescriptions for kids and adolescents and increasing suicide rates in youth. This became accepted wisdom. But in our paper, we reviewed the research and concluded that the original black box warning should not be merely dismissed.

Dr. Feder: This black box warning was, and still is, a big deal for those of us working in child and adolescent mental health. What are your thoughts on it Mara?

Mara: Yeah this is a really big problem and a big concern especially in the time of pandemic that we need to address with our clients.

Dr. Feder: We’re handling it with our families in our practice now. There are aspects of this we definitely need to understand better. First of all: is there really a correlation between antidepressant use and suicidality in kids? 

Mara: Dr. Spielman’s team dug into the studies and there’s some important nuance to our understanding of this issue.

Dr. Feder: Exactly. Here’s what he had to say about the data surrounding the black box warning.

Dr. Spielmans: We did a selective literature review of papers from 1990 to 2018. We found a large increase in the number of antidepressants prescribed from the 1990s up to 2004. After the black box warning in the US in 2004, this decreased slightly for a while, but returned to the previous rates by 2009 and has continued to rise. Meanwhile, the US suicide rate in teens has been rising over the past decade. We also found that at the time of the US warning in 2004, the prescribing rate plummeted in the UK but there was no increase in suicides. For some reason, less antidepressant prescribing was related to somewhat higher rates of suicide in the US, but not in the UK.

Mara: Why would the UK show different trends?

Dr. Feder: Dr. Spielmans attributes that to potentially cherry picked data on US suicidality. 

Dr. Spielmans: a very influential paper in 2007 by Robert Gibbons and his team looked at one particular year (2003–2004), and reported that there was a decrease in antidepressant prescriptions and an increase in suicides during that time frame (Gibbons RD et al, Am J Psychiatry 2007;164(9):1356–1363). But every year there will be fluctuations or blips in the data: more or fewer suicides, more or fewer antidepressant prescriptions. Therefore, accurately studying these trends requires a time series of several years of data.

Dr. Feder: And that wasn’t the only problem they found with Gibbons’ research. 

Dr. Spielmans: Another paper from the Gibbons team analyzed the clinical trials of Prozac (fluoxetine) and claimed that these studies showed no increase in suicide risk due to this antidepressant. But the measure of suicide risk used one item from the Children’s Depression Rating Scale (CDRS) (Gibbons RD et al, Arch Gen Psychiatry 2012;69(6):580–587). The FDA and even GlaxoSmithKline say that’s not a good measure of suicide risk (https://pubmed.ncbi.nlm.nih.gov/16553530; www.tinyurl.com/yx8hjcsk). Another SSRI, Paxil (paroxetine), has in fact been associated with increased risk—several papers have reported higher rates of suicidality, with one study showing 3.4% vs placebo at 0.9%.

Mara: There’s also an issue differentiating between milder depression and severe depression. 

Dr. Spielmans: That’s an important distinction. In the US, antidepressant prescriptions were reduced among kids with milder depression, but not among severely depressed kids (https://ps.psychiatryonline.org/doi/10.1176/appi.ps.201700089), so we don’t know if decreased use of antidepressants leads to increased suicidality in this population.

Dr. Feder: When you put all this data together, it becomes clear that the relationship between antidepressants and suicidality is much more complex than the initial black box warning indicated. Those time-series observational studies don’t tell the full picture. Simply looking at antidepressant prescriptions and comparing that to suicide rates doesn’t help us understand what’s going on, and doesn’t help us understand how to talk to our patients about this potential link. 

Mara: Dr. Ignaszewski’s research found no increased suicidality with antidepressant treatment. Here’s what she had to say about those findings.

Dr. Ignaszewski: Our paper initially was conceived as providing an update on the effectiveness of new antidepressants for treatment of pediatric depression over the last decade. As we were going through the papers, we noticed that there was a shift in methodological assessment for treatment-emergent suicide. Namely, newer research was systematically utilizing the Columbia-Suicide Severity Rating Scale (C-SSRS) to assess both baseline and treatment-emergent suicidal ideation, as opposed to the CDRS or self-report, which were used in past studies. The more recent data, which used a more sophisticated measure of suicidality, indicated that there was no increased risk of suicidality in the active medication arms versus placebo.

Mara: So we have to wonder, how is it that Dr. Spielmans’ team found an association and Dr. Ignaszewski didn’t? She has thoughts on that too.

Dr. Ignaszewski: Glen was able to drill down deeper into the data and uncover suicidal events that were not apparent in our analysis. He and his team identified that some of the data were incorrect or misattributed to placebo.

Mara: So here we are. I feel like we have a more educated understanding of the research on this than we did a decade ago. At the end of the day there’s only one thing that matters. How does this affect the way we treat patients?

Dr. Feder: Exactly. Here’s what Dr. Ignaszewski advised on that.

Dr. Ignaszewski: Context is crucial, and this is something that I review with primary care and pediatricians all the time. Suicidal ideation travels with other symptoms of depression, such as worsening functioning, sadder mood or irritability, progressive anhedonia, and not wanting to spend time with friends or on enjoyed activities. Firstly, we want to assess whether these symptoms are also present, which would stratify our approach and we might continue or increase the medication rather than decreasing the dose or stopping it. Secondly, in any scenario, we would want to provide more frequent check-ins for the patient and family, and thirdly we’d work on safety planning. We help the child and family learn how to manage those thoughts and feelings, maintain safety and seek additional support, rather than reflexively changing medication dosage.

Dr. Feder: And Dr. Spielmans had this advice on talking to patients.

Dr. Spielmans: We need to let patients and their parents know that if suicidality emerges, it could be drug induced. If suicidality is automatically attributed to depression getting worse, then prescribers might increase doses or augment treatment in some other way. But if suicidality is viewed as possibly medication related, prescribers might take more thoughtful approaches, such as consideration of dose reduction, emphasizing psychotherapeutic approaches, and scheduling more frequent check-ins.

Mara: This goes back to a thorough informed consent process. If listeners haven’t heard our episode on that, it’s linked in this episode description. 

Dr. Feder: Yes, we have a specific process in place with informed consent to talk about the advantages and risks of medication. This is an extremely important risk that needs to be discussed and evaluated on an ongoing basis. It’s also something that clinicians need to put in the context of the patient’s diagnosis, environment, and background.

Mara: They had an interesting discussion about the differentiation between SSRIs for anxiety and depression. Take a listen. 

Dr. Spielmans: For anxiety, you can make a good case that SSRIs can be beneficial. With depression, it gets trickier. It’s more effective than a placebo, but usually by a pretty small amount.

Dr. Ignaszewski: Right. We are talking about more severe depression. Over-pathologizing normal sadness confuses research findings because these research subjects have high placebo response rates, so we might see very limited separation from active treatments. So when I am talking to patients and families, I try to differentiate normal sadness from pathological depression by focusing on functional impairment. I look for a major departure from what their life has been like, their activities and their overall developmental trajectory, perhaps no longer going to school. Medication can be indicated in these situations to get things back on track.

Dr. Spielmans: I agree that impairment can be a gauge as to who needs treatment. In terms of studying the risks of untreated depression, you’d need a group of children and adolescents with depression whose families do not want treatment but ar e willing to participate in a study. Even for adults, the research on untreated depression is sparse, especially in the long term. I think it’s dicey to guess at the risk of suicides among children and adolescents with untreated depression. Not all youth who die by suicide are suffering from underlying depression, and many children/adolescents who die by suicide have multiple mental health struggles, so it’s hard to necessarily say that untreated depression by itself was the cause of suicide.

Dr. Feder: I found this entire interview to be extremely helpful. Unfortunately there’s no definitive answer on when or how to prescribe antidepressants, but there is a clear call for awareness about potential suicidality and also a clear call to read the research carefully and critically when we’re making clinical decisions.

Mara: The detailed analysis of these studies shows me that there’s a lot left to find out about this issue and we need to consider that as clinicians every time we work with our patients.

Dr. Feder: We have to put our patients’ interests first. There’s a specific part of the discussion where Dr. Spielmans’ runs through some of the startling instances of incorrect data or manipulated date. Take a listen.

Dr. Spielmans: My research dissects studies. In this case, one escitalopram trial attributed two suicidal events to placebo, but—and you had to read the article carefully to see this—both events happened after the people had stopped taking placebo and had started taking escitalopram in the community (https://pubmed.ncbi.nlm.nih.gov/24041408). It’s hard, potentially impossible, to casually read an article and pick up on those things without doing a deeper dive into the numbers. I’ve also read a lot of internal drug company documents, and when a clinical trial is written up, it is written  with marketing in mind first, science second. It wasn’t until lawsuits were filed and internal documents were released that it became clear there were suicide-related events that were not reported in journal articles (https://pubmed.ncbi.nlm.nih.gov/12835239; https://pubmed.ncbi.nlm.nih.gov/18792536). We’re told to practice evidence-based medicine, but if the evidence itself is not accurate, that’s a problem.

Dr. Ignaszewski: I’m so thankful for this discussion and Glen’s paper because it was so eye opening for me. As providers, we need to be more aware of these practices and go further to teach trainees about this. We need non–industry funded ­studies by national health organizations and others to get the data for making our decisions, and to reduce reporting with clear conflicts of interest.

Mara: So often these discussions come down to a call for better, more independent research.

Dr. Feder: And until we get better data, it’s on us to keep these questions in mind and communicate this issue clearly with patients and families so we can be effective partners in preventing any self-harm while treating their depression.

This full interview is available for subscribers to read in The Carlat Child Psychiatry Report. Hopefully people check it out. Subscribers get print issues in the mail and email notifications when new issues are available on the website. Subscriptions also come with full access to all the articles on the website and CME credits. 

Mara: And everything from Carlat Publishing is independently researched and produced. There’s no funding from the pharmaceutical industry. 

Dr. Feder: Yes, the newsletters and books we depend entirely on reader support. There are no ads and our authors don’t receive industry funding. That helps us bring you unbiased information you can trust.