Essential Reads: What is the Best Antidepressant to Use During Pregnancy?

By MGH Center for Women's Mental Health | May 19th, 2021

"This is a question we often hear.  One of the challenges in answering this question is the interpretation of the word “best”.  On one hand, the best antidepressant is the one that is the most likely to be effective.  On the other hand, the best antidepressant is the one that carries the least risk when used during pregnancy. What this means is that there is no single answer.  Each situation is different, and our recommendations are based on a careful assessment of the patient’s course of illness, treatment history, past medication trials, and the most up-to-date information on reproductive safety. Added to this calculation is the understanding that untreated depression also carries some risk in terms of maternal well-being and has been associated with worse pregnancy outcomes.  

Stay with the Same Treatment or Switch?
We often meet with women who have switched to a different antidepressant medication in preparation for pregnancy.  Other women make a switch when they discover they are pregnant.  These switches are motivated by the belief that there is a “safer” medication to be used during pregnancy.  The reality is that most of the antidepressants taken by women today are relatively safe and carry a very low risk to the developing fetus.  What separates one antidepressant from another is that some medications have more data to support their reproductive safety than others.  But even this distinction is disappearing; we have data to support the use of most SSRIs (with less data on fluvoxamine or Luvox), the SNRIs duloxetine (Cymbalta) and venlafaxine (Effexor), and bupropion (Wellbutrin). Tricyclic antidepressants, although not commonly used today, also have data to support their reproductive safety.  

MAO Inhibitors: 
We have very little data on the reproductive safety of the MAO inhibitors. In addition, MAO inhibitors may have serious interactions with other medications frequency used during pregnancy and labor and delivery, specifically medications used to manage pain, such as nalbuphine (Nubain) and meperidine (Demerol).  In women taking these medications, we are likely to suggest switching to another antidepressant with a better reproductive safety profile.  

Mirtazapine (Remeron):  
At this point, we have less data on the use of the newer antidepressants. There is some data on mirtazapine, with the most recent study including 334 cases of neonates with prenatal exposure to mirtazapine.  While these data are reassuring and there is no indication that mirtazapine carries significant teratogenic risk, the number of mirtazapine exposures remains small.  Ideally we would like to have data from 600-700 exposures to get a better estimate of risk.  Making decisions regarding safety on studies with small sample sizes can lead to miscalculations of risk in either direction.

Other Antidepressants: 
The data is even more limited with regard to the use of vortioxetine (Trintellix), vilazodone (Viibryd), levomilnacipran (Fetzima). If there are effective alternatives, we typically recommend switching to another antidepressant.  
In settings where we have limited data regarding the reproductive safety of a particular antidepressant, we may consider switching to an antidepressant with a better characterized reproductive safety profile.  It is important, however, to carefully consider the benefits and risks of making this switch. With any switch, there is the risk of relapse when making a change in the maintenance treatment. Thus, there are situations where we recommend continuing an antidepressant with limited reproductive safety information because there are no effective alternatives and the risk of relapse is significant.  

What About Zoloft? Isn’t Zoloft the Safest?
At some point in the early 2000s, there emerged the belief that sertraline (Zoloft) was the safest antidepressant to use during pregnancy, and many women taking other antidepressants were encouraged to switch to sertraline during pregnancy.  It is somewhat unclear where this opinion came from — maybe one paper suggesting lower placental passage of sertraline compared to other antidepressants; however, there is and never was any solid data to support the assertion that sertraline is safer or the safest antidepressant.  Reflexively switching women to sertraline puts women at risk for recurrent illness.  

While sertraline is effective for the treatment of depression and anxiety and is a reasonable choice for many women, one problem with sertraline is that it tends to be under-dosed. The typical starting dose is 50 mg; however, many individuals will need 150 mg to 200 mg to effectively manage their symptoms.  Especially when sertraline treatment is initiated in the primary care setting, we often see women whose dose is too low to effectively manage their symptoms.   

What About Paxil? Doesn’t It Cause Heart Defects?
The most current data regarding the use of paroxetine (Paxil) during pregnancy does not indicate an association between the use of paroxetine during pregnancy and risk for cardiovascular malformations.  However, in 2006, GlaxoSmithKline (GSK) elected to change product label warnings for the antidepressant paroxetine (Paxil), advising against the use of this drug by women who are pregnant. This decision was based on two preliminary studies which suggested a small increase in the risk of cardiovascular malformations among infants exposed to paroxetine in utero. For many years, this concern regarding risk of heart defects resulted in recommendations that women taking paroxetine should either stop paroxetine or to switch to a different antidepressant during pregnancy.

However, in 2008, a study from the Motherisk Program in Toronto reported on the outcomes of over 3000 paroxetine-exposed infants and found no association between the use of paroxetine during pregnancy and increased risk of cardiovascular malformations.  Nonetheless, some women and their treaters continue to feel uncomfortable with the use of paroxetine during pregnancy. Furthermore, many websites (including reputable sites like the Mayo Clinic) continue to urge women to avoid paroxetine during pregnancy because of the risk of malformations. 

At this point, we typically do not recommend switching from paroxetine to another antidepressant for pregnancy. Although paroxetine is an SSRI, there are definitely situations where an individual may respond better to paroxetine than to other SSRIs. Thus, switching to a different antidepressant may increase risk for relapse. 

What About Lexapro? And Pristiq?
There are some newer antidepressants that are derived from older parent antidepressants.  For example, citalopram (Celexa) is a racemic mixture, composed of R- and S-enantiomers (or mirror images) of citalopram.  While the S-enantiomer is clinically active, the R-enantiomer is not.  Escitalopram or Lexapro contains only the active S-enantiomer.  Because the S-enantiomer is contained in the original citalopram formulation, we can infer that the reproductive safety of escitalopram (Lexapro) is the same as that of citalopram (Celexa).
Another example is desvenlafaxine or Pristiq.  For venlafaxine to be effective as an antidepressant, it must first be metabolized by the body to desvenlafaxine.  Pristiq contains only the active metabolite desvenlafaxine.   Because desvenlafaxine is a metabolic byproduct of the original venlafaxine formulation, we can infer that the reproductive safety of desvenlafaxine (Pristiq) is the same as that of venlafaxine (Effexor).

The Bottom Line
No two situations are identical; thus, we must carefully consider each woman’s clinical history and preferences in order to select a treatment plan that makes sense.  Ideally this discussion should occur long before a woman is pregnant, so that there is ample time to consider the various options and to make changes, if necessary.  

When we meet with women to discuss the use of antidepressant medications during pregnancy, we typically consider a number of issues:

1. Determine the risk of recurrent illness: Has she had one episode of depression or does she have recurrent depression? If she has attempted to discontinue antidepressants in the past, how long was she able to remain well without medication? If she has had prior pregnancies, what happened to her mood during pregnancy and the postpartum period?
2. Assess the severity of previous episodes of depression: Did the depression contribute to missed days of school or work? Psychiatric hospitalization? Suicidal ideation? Self-harm? Suicide attempt?
3. Review past medication trials: What antidepressants have been effective in the past? Which antidepressants have been ineffective? Assess dose and duration of treatment to determine if the trial was adequate.  
4. Identify factors that may mitigate risk: Has psychotherapy been helpful? Is this an option for decreasing risk for relapse? What about other non-pharmacologic interventions: mindfulness, meditation, yoga, acupuncture, exercise?
5. Discuss options for pharmacologic treatment during pregnancy: What are the antidepressants most likely to maintain stable mood during pregnancy? What is the medication with the best characterized reproductive safety profile? Does it make sense to maintain or to switch to a different antidepressant? Even if the woman ultimately decides that she would like to avoid medications during pregnancy, it is important to discuss options for treatment, in case she relapses during pregnancy and would like to resume treatment. 

We now have data to support the reproductive safety of a large number of antidepressants.  
The perinatal psychiatry consultation should be viewed as a collaborative venture, where provider and patient decide together what is the best option for treatment during pregnancy."

-​Ruta Nonacs, MD PhD