Antidepressant Treatment During Pregnancy
Commentary
by Margaret Spinelli, M.D.
American Journal of Psychiatry. 2012 169:121-124.
[full text on-line]
A behavioral health outpatient program recently decided that psychiatrists would no longer be permitted to provide new prescriptions for antidepressants to pregnant women because the sponsoring institution had determined that the risk was too high. As a psychiatrist specializing in the treatment of women in the perinatal period, I am one of many practitioners who must frequently decide whether or not to use medication to treat depressed pregnant women.Currently, the medical literature contains studies of more than 20,000 pregnancy outcomes for women exposed to antidepressants. This literature has been helpful in identifying possible effects of this exposure on the outcome of pregnancy. The results of studies that demonstrate increased risk for adverse pregnancy or birth events are frequently publicized in the media, which has resulted in many pregnant women refusing medication. Some law firms have seized on this information to seek plaintiffs to bring lawsuits. Many clinicians hear of positive studies through the media or see advertisements from law firms, scan the medical literature for abstracts, and may conclude that the risks of medication to the mother and fetus outweigh possible benefits. However, negative studies receive minimal media attention…
I don’t have any illusions that I can single-handedly catch all the industry seeding of our literature, but it does make me feel like I’m doing my part to look for it. The years of letting those articles slide under the radar has contributed to a lot of corruption and over-medication. Then sometimes I run across Commentaries and I usually read them, even if the topic isn’t particularly interesting to me, just to see what they’re about. That’s how I got to reading this one. By the first paragraph, it was clear that Dr. Spinelli is in the give antidepressants to pregnant women camp, with the usual preventive medicine outweighs the risk arguments. I don’t particularly like those arguments. They presume that anti-depressants are specific, work well, and will halt the negative consequences of untreated depression – a simplistic and indefensible position. These articles are usually like this one – filled with hypothetical arguments, categorical statements, and very little in the way of science. This one can only be considered a strongly held opinion piece – motives unspecified. I was thinking that it’s not particularly compelling, but I guess it’s her prerogative to say what she thinks.
We saw an inappropriate decline in the prescription of antidepressants for adolescents and young adults because of a Food and Drug Administration black box warning about suicidality. However, untreated depression itself has a far greater impact on suicidal behavior than the adverse effects of the antidepressants. Psychiatrists have generally used appropriate judgment in prescribing antidepressants and psychotherapies for this patient population, but other physicians did not. We now need to communicate clearly about the risks and benefits of treatment for depressed pregnant women if we wish to avoid similar adverse consequences to their well-being and the well-being of their infants.
Here are the underwhelming efficacy graphs for Prozac [2], Paxil, and Zoloft – "CRO Charts" [pretty loud coi…]. By the way, that’s the famous Study 329 in the lower left:
Impact of Publicity Concerning Pediatric Suicidality Data on Physician Practice Patterns in the United States
by Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg
Archives of General Psychiatry. 2007 64(4):466-472.
If you don’t recall these articles, take a look [the apogee…, pretty loud coi…, tortured numbers…]. Within a year, three of the four non-Quintiles authors on the first study were busted for unreported personal income from industry and all four were on POGO’s list of authors using ghost-writers. Three were Department Chairmen who "stepped down" early under pressure in the coming years. None of them were Child and Adolescent Psychiatrists. I called my post "the apogee" because It seemed to me it was the pinnacle of the arrogance of the times. I named the other studies "tortured numbers" for reasons easily seen. This looked like a thinly disguised, industry-lead campaign against the FDA because the FDA warning resulted in a fall in sales of anti-depressants. Doctors and Patients listened to the FDA! Good for them.
Decline in Treatment of Pediatric Depression After FDA Advisory on Risk of Suicidality With SSRIs
by Anne M. Libby; David A. Brent; Elaine H. Morrato; Heather D. Orton; Richard Allen; and Robert J. Valuck
American Journal of Psychiatry 2007 164:884-891.
[full text on-line]
Objective: In October 2003, the U.S. Food and Drug Administration (FDA) issued a public health advisory about the risk of suicidality in pediatric patients taking selective serotonin reuptake inhibitors (SSRIs) for depression. This study used data from a large national pediatric cohort to examine patterns of diagnosis of depression, prescription of antidepressants, prescription of pharmacological alternatives to antidepressants, and use of psychosocial care before and after the FDA advisory was issued.
Method: A large pediatric cohort with newly diagnosed episodes of depression was created from a national integrated claims database of managed care plans from October 1998 to September 2005 (N=65,349). Time-series models were used to compare diagnosing and prescribing trends during the 2 years after the FDA advisory and the expected trends based on data from the 5-year period preceding the advisory.
Results: From 1999 to 2004, pediatric diagnoses of depression increased from 3 to 5 per 1,000. After the FDA advisory was issued, the national rate decreased to 1999 levels, a significant deviation from the historical trend. Pediatricians and nonpediatrician primary care physicians accounted for the largest reductions in new diagnoses. Among patients with depression, the proportion receiving no antidepressant increased to three times the rate predicted by the preadvisory trend, and SSRI prescription fills were 58% lower than predicted by the trend. There was no evidence of a significant increase in use of treatment alternatives (psychotherapy, atypical antipsychotics, and anxiolytics).
Conclusions: The FDA advisory was associated with significant reductions in aggregate rates of diagnosis and treatment of pediatric depression.
Mr. Allen, Dr. Libby, Ms. Orton, Dr. Morrato, and Dr. Valuck report an unrestricted investigator-initiated research grant from Eli Lilly and Company; Dr. Valuck also is an advisory board member for Eli Lilly. Dr. Morrato has received research support from Janssen and Pfizer. Mr. Allen has received research support from GlaxoSmithKline. Dr. Brent reports no competing interests.Supported by an investigator-initiated grant from Eli Lilly and Company to fund the access fees to the independent PharMetrics database and salary support for the investigators.
Strengths of this study include the patterns of community care observed in the data, as well as implications for future policies on drug risks. The FDA’s drug safety policy has moved toward broader and more proactive communication of new safety warnings for marketed drugs. The FDA has emphasized its "aggressive development of electronic health information" to directly alert patients and providers about the risks of prescription medications. The agency has issued draft recommendations for a "Drug Watch" system to disseminate emerging drug safety information as safety signals emerge and before causality is determined. The results of our study suggest a need for public health interventions to ease unintended but predictable changes in treatment patterns that may increase "the risk of doing nothing".
So back to Dr. Spinelli’s Commentary. She declares no competing interests, and for all I know may well be passionate about using antidepressants during pregnancy for the best of motives. But if that’s the case, I’d prefer that she divert her zeal into some solid epidemiological research rather that speculating about the studies done by others. But that’s neither here nor there. My beef is that she has taken an industry campaign against the FDA Warnings about the adverse effects of SSRIs in adolescents at face value. She makes definite statements like "However, untreated depression itself has a far greater impact on suicidal behavior than the adverse effects of the antidepressants" without giving any references as if it’s the truth, rather than the tired party line of drug companies and their KOLs.
It’s irresponsible to suggest that we should use these drugs in pregnancy based simply on someone’s opinion. And it’s suspect to use a questionable, industry driven campaign heavily tainted with blatant conflicts of interest as a template on which to hang our logic. Pregnant women represent a large market for antidepressant manufacturers, just like children and adolescents. After the last twenty-five years of stealth and deceit from that quarter, if she wants to convince anyone of her point, she’s going to have to come at it from another direction.
I was just discussing w/my psychiatrist the pros and cons of going off Effexor before attempting pregnancy vs. during the pregnancy. There was no question between us that I would be controlling my depression with talk therapy primarily during most of the hypothetical pregnancy – and probably choosing drugs over breast feeding to stave off the probable postpartum. Do you know of any studies that deal with the effect of antidepressants on early (first trimester) fetal development? I know that’s when a lot of neurological stuff happens.
came across this one on twitter: A Fresh Look At Antidepressants Finds Low Risk Of Youth Suicide http://n.pr/z07GcR Major authors same in both studies mentioned.
My response: I must question when a statistician changes the criteria to make the data reach a different conclusion…especially a Pfizer lapdog
article here: https://www.npr.org/blogs/health/2012/02/06/146481573/a-fresh-look-at-antidepressants-finds-low-risk-of-youth-suicide?ft=1&f=1001
journal paper here: http://archpsyc.ama-assn.org/cgi/content/abstract/archgenpsychiatry.2011.2048
I thought you might be interested in looking this one over, and possibly commenting on it’s conclusions.
Rachel,
I’m a non-expert on this topic. But when I wrote this, I ran across a number of articles. This one from Israel seemed to be a good review and had innumerable references [along the right side]. You might take a look. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236415/?tool=pubmed.
I’ll be honest and say if my daughter asked me the same question, I’d advise her to be drug free during the first trimester no matter what she read, because the studies are so variable and the opinions so colored by other factors. That’s just my nature when it comes to medicines – safety first.
Stan,
Thanks for sending this. I’ll look at it in my next free spot. I can tell you in advance the problem I’ll have with it. I’ve personally seen the akithisia, agitation, and suicidality in several adults and one adolescent boy with my very own eyes in patients whose prescriptions I wrote with my very own ball point. It was scary stuff, particularly the adolescent. When you see something happen in front of you, it leaves a strong imprint. So I’m a believer from n=1 experience. But I’d like to see what this series has to say.
As you noted, the central claim of Dr. Spinelli in her opinion piece is “… untreated depression itself has a far greater impact on suicidal behavior than the adverse effects of the antidepressants.†I looked into this question some years ago, just after the furor got going. Using reasonable epidemiological numbers, I came up with the conclusion that there was probably no net effect one way or the other. That is, any reduction of suicide by the drugs in treated depressive episodes would be balanced by the increased suicidal pressure that the drugs induce in some patients. Readers can access the correspondence on this point in JAMA, December 1, 2004 (PubMed ID 15572711).
Dr. Spinelli’s piece illustrates the problems of narrative reviews. Chief among these problems is their innumeracy, followed by their selectivity.
innumerate (ɪˈnjuËmÉ™rɪt)
— adj
1. having neither knowledge nor understanding of mathematics or science
— n
2. an innumerate person
in’numeracy
— n
Dr David Healy has posted on the antidepressant study
http://davidhealy.org/coincidence-a-fine-thing
“Coincidence a fine thing”
It’s simply Pharma fightback:
Suicidal Thoughts and Behavior With Antidepressant Treatment
Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine
Robert D. Gibbons, PhD; C. Hendricks Brown, PhD; Kwan Hur, PhD; John M. Davis, MD; J. John Mann, MD
Arch Gen Psychiatry. Published online February 6, 2012. doi:10.1001/archgenpsychiatry.2011.2048
ABSTRACT
Context The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults.
Objective To determine the short-term safety of antidepressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms.
Data Sources All intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride.
Study Selection All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine.
Data Extraction The suicide items from the Children’s Depression Rating Scale–Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations.
Data Synthesis Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior.
Conclusions Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication. To our knowledge, this is the first research synthesis of suicidal thoughts and behavior in depressed patients treated with antidepressants that examined the mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.
Financial Disclosure: Dr Gibbons has served as an expert witness for the US Department of Justice, Wyeth, and Pfizer Pharmaceuticals in cases related to antidepressants and anticonvulsants and suicide. Dr Brown directed a suicide prevention program at the University of South Florida that received funding from JDS Pharmaceuticals. Dr Mann has received research support from GlaxoSmithKline and Novartis.
A META-ANALYSIS OF…
… longitudinal data for RCTs of fluoxetine hydrochloride conducted by Eli Lilly and Co, the Treatment for Adolescents With Depression Study (TADS) of fluoxetine in children by the National Institute of Mental Health,3 and adult studies for venlafaxine hydrochloride conducted by Wyeth.
TADS DISCLOSURES:
Financial Disclosures: Dr March has served on the speaker’s bureau for Pfizer and Lilly and has received research support from Lilly, Pfizer, and Wyeth. Dr Findling has received research support from Bristol-Myers Squibb, Forest, GlaxoSmithKline, Lilly, Nature’s Herbs, Organon, Pfizer, Solvay, Somerset, and Wyeth; been a consultant for Bristol-Myers Squibb, Forest, GlaxoSmithKline, Lilly, Pfizer, Somerset, and Wyeth; and served on the speaker’s bureau for Bristol-Myers Squibb, GlaxoSmithKline, Lilly, and Wyeth. Dr Waslick has received research support from Lilly. Dr Walkup has received research support and honoraria from Lilly. Dr Kastelic has received honoraria from Pfizer. Dr Kratochvil has received reseach support from Lilly, Forest, and GlaxoSmithKline; been a consultant for Lilly; and served on the speaker’s bureau for Lilly. Dr Harrington has received research support from Lilly, Pfizer, and Astra-Zeneca. Dr Leventhal has been a consultant, received research support, and served on the speaker’s bureau for Lilly. Dr Emslie has received research support from Lilly, Organon, and RepliGen; been a consultant for Lilly, GlaxoSmithKline, Forest Laboratories, Pfizer, and Wyeth-Ayerst; and served on the speaker’s bureau for McNeil.
Re: “However, untreated depression itself has a far greater impact on suicidal behavior than the adverse effects of the antidepressants.”
Show me the numbers.
Show me the decline in suicide rates with antidepressant drugs.
The numbers aren’t there.
They don’t exist.
Antidepressants do not “save lives.”
If antidepressants “saved lives” we would see a decrease in suicide rates since their introduction into medicine… significant reductions, now that 1 in 10 people in this country take them.
The ole “they save lives” argument doesn’t hold water.
It’s a myth.
It’s based upon nothing!
Duane Sherry
discoverandrecover.wordpress.com
I have never read anywhere on this issue of suicidality by antidepressants if the patient population that showed said response were treated by psychiatrists, or nonpsychiatrists. That said, with the undeniable fact that over 70% of antidepressants by in large have been written by nonpsychiatrists for at least the past 5 or more years, I think it is fair to say that approximately 2/3s of the suicidal population were being managed by people not fully trained to manage depression. So, is the issue of suicidality really due to antidepressants, or, from mismanagement of an illness that was not going to be effectively treated by medication alone, and let’s be fully honest and candid, how many non psychiatrist prescribers advised and followed up on patients getting into psychotherapy while starting on medication? And, how many patients were appropriately titrated on most if not all antidepressants? To this day there are still providers who think the daily dose is started at day 1!
But, this does not excuse the profession of psychiatry from responsibility. When a profession abdicates much of it’s professional standards to other clinicians in mental health and allows itself to be marginalized into basically just one intervention, an act of omission is fairly much as poor as one of commission.
By the way, the pregnancy debate with use of antidepressants is just pathetic. My favorite ongoing experience is having patients referred to me by OBGYNs who are ADAMANT that the patient needs to be on medication for mood management, but, will let the patient wait weeks if not a month or more to be seen by the psychiatrist to get meds started. I mean, if it such a clinical urgency, and we hear endlessly this alleged defense by other physician providers that they will start meds for patients knowing there will be a wait, why do OBs not follow suit?
Catch the pun at the end of that last sentence? It is to avoid the suit. Catch any of those pathetic ads about “if you had a child who had birth defects while on Zoloft, Paxil, or other antidepressants, you may be entitled to compensation.” And one ad I caught a couple of weeks ago on Fox News in the AM actually had this as the number to call: 1 800 BAD DRUGS!
One last loose association before I go, how about the growing controversy of PPACA now mandating the Catholic Church health care systems must allow BCPs be dispensed to employees interested in said meds. And there it is, the first boil of the ugliness of mandated care consequences. If the pathology spreads, which it will, one helluva pustule laden legislation will be viewed, eh?
Dr. Hassman,
I agree with your comments about what’s taking place with mandated care.
“First, they came after the Catholics” –
http://townhall.com/columnists/michellemalkin/2012/02/01/first_they_came_for_the_catholics
Duane
Duane
Someone should tell Dr. Spinelli that there are other treatment options for depressed women during pregnancy– psychotherapy is one of them. DUH!!!
I’ve always found the argument that untreated maternal depression is a worse risk to the child than iatrogenic damage during gestation to be a very strange one. This presumes iatrogenic damage to the developing fetus is temporary and maternal depression cannot be treated by any other means, as Tom pointed out above.
(Hey, how about support groups for expecting mothers and newly delivered mothers? The anxiety of isolation has a lot to do with maternal depression. Instead of drugs, why not give mothers a network of social support?)
Heart and lung defects are forever.
Anecdotally, my gynecologist, perhaps the premier obstetrician in the San Francisco Bay Area, says she’s seen antidepressant withdrawal syndrome both in her adult patients and in the babies she’s delivered. Strange that an OB/GYN can perceive these cases, but many psychiatrists never do. (She’s given up prescribing psychiatric medications for her patients and is outraged by being tricked into prescribing them for PMS etc.)
The assumption that when the baby stops crying and convulsing, its antidepressant withdrawal experience is over is merely wishful thinking. From adult experiences, we know withdrawal symptoms can last months.
The long-term effects of strong psychoactive drugs on the developing nervous system are unknown, but the effects of anesthesia have been shown to be deleterious.