​“You might’ve noticed I’ve got a slight weight problem.  I went to this doctor.  Well, he told me I swallowed a lot of aggression…along with a lot of pizzas.”
 
You might recognize this quote from the 1981 movie Stripes. I sometimes think of Dewey Oxberger, played by John Candy, when prescribing psychotropic medications that can cause weight gain. We all know the second generation antipsychotics can lead to our patients swallowing a lot of pizzas. However, things are less clear regarding antidepressant medications. We know that risk of weight gain can be a major factor in a teen’s decision to start an antidepressant medication, and weight gain can lead to noncompliance. The aim of this article is to review the risk of weight gain with antidepressants commonly prescribed in the primary care setting.

Data points to a definite risk of mild weight gain with “long term” treatment with SSRI medication (meaning six months or more). This is less likely in treatment of six months or less. When weight gain does occur with short term SSRI treatment, the rates are comparable with placebo. This does not apply to Paroxetine (Paxil), which is more likely to cause weight gain than the other SSRIs in short or long term treatment.
In a 6-month placebo controlled trial (N=284) paroxetine showed significant weight gain (increase 7% or greater body weight) in 25.5% of patients. Sertraline (Zoloft) showed 4.2% significant weight gain and fluoxetine (Prozac), which showed 6.8%. Fluoxetine may show a transient weight loss in the initial phase of treatment.

There is limited data indicating citalopram (Celexa) and escitalopram (Lexapro) may cause higher rate of weight gain than sertraline and fluoxetine, though this is likely not significant.
Mirtazapine is well known to cause weight gain in the short and long term. Often this is prescribed to stimulate appetite. Weight gain is related to its histamine H1 and serotonin 2C receptor activity. Weight gain is often seen in the first four weeks of treatment.

As far as SNRI medication, Venlafaxine (Effexor) has been shown less likely than SSRI to cause weight gain. In a 52-week open-label study, duloxetine (Cymbalta) treated patients had a mean weight gain of 1.1 kg at endpoint. Duloxetine-treated patients experienced weight loss after short-term treatment, followed by modest weight gain on longer-term treatment.
​
Overall, antidepressants, aside from paroxetine and mirtazapine, and tricyclics, appear to have minimal large scale effects on body weight. Fluoxetine appears to be the SSRI least likely to cause weight gain. 

At times, psychotropic decision making can feel more like an art form than science. Decision trees based on various trials inform the prescriber, but often are based on having the correct diagnosis in the first place. Lamotrigine is increasingly prescribed in when the primary diagnosis is “Emerging Borderline Traits” or Borderline Personality disorder (BPD). Compared to alternative mood stabilizers, especially the atypical antipsychotic class, it appears to have a more tolerable side effect profile with potential for benefit. While lamotrigine is just one of many medications used off label in treating symptoms of BPD, it warrants investigation.
 
In 2018 the UK National Health Service (NHS) attempted to clarify this very point with the “

• …test whether or not prescribing lamotrigine in addition to usual treatment reduces symptoms of this condition, improves social functioning and quality of life, reduces the incidence of suicidal behavior, reduces the level of alcohol and substance misuse and lowers the amount of antipsychotic and other psychotropic medication that people are prescribed. 

 
LABILE resulted in over 270 patients with BPD separated into a lamotrigine arm and placebo arm. Each arm received normal treatment as well. Review of the study demonstrate reliable and valid results. Patients were recruited from NHS treatment centers and demonstrated severity across the spectrum of the condition.
 
To put it simply, in as real world a study as possible, with the largest number of patients yet, lamotrigine did not hold up the initial suggestion of benefit from earlier research. Results between placebo and lamotrigine treatment were equivocal. Levels of depression, the likelihood of self-harming or suicidal behavior and likelihood of problem drug or alcohol use were all comparable across the groups at follow-up. Social functioning was also equivalent across groups. 
 
Additionally, medication compliance was poor for all patients after 12 weeks, with only thirty three percent demonstrating consistency. In a medication where inconsistent/rapid titration can be life-threatening this can be especially concerning. The indication is that lamotrigine, similar to all other medications, does not treat or alleviate BPD symptoms. It adds cost and risk. 
 
A notable risk of lamotrigine is that of Steven’s Johnson Syndrome, a serious and life threatening blistering rash of mucosa and skin. When the medication is titrated too quickly, the risk increases markedly. After a two days of missed medication the 2 week titration schedule for lamotrigine must be started again. Poor compliance with
this medication certainly places patient at greater risk.
 
On the other hand, there is some reason to conclude hopefully regarding BPD. The interaction with the physician was stabilizing. The indication of having a legitimate treatable condition was validating. However the lamotrigine did not add to this benefit any better than an inert placebo.  
 
BPD warrants treatment. Patients with the disorder have a completed suicide rate greater than fifty times the general population. They utilize emergency and clinic resources to an extensive degree. Anti-depressants fair worse than placebo. Benefits of atypical anti-psychotics match placebo. Sadly, lamotrigine, much like many medications before it, once scrutinized does not meet the hope of its initial small studies and open label trials.
 
Therefore do not fall into the trap of avoiding the valid and successful treatment of Dialectical Behavior Therapy and Mentalization Based Therapy.
 
Crawford MJ, Sanatinia R, Barrett B, et al. Lamotrigine for people with borderline personality disorder: a RCT. Southampton (UK): NIHR Journals Library; 2018 Apr. (Health Technology Assessment, No. 22.17.) Available from: https://www.ncbi.nlm.nih.gov/books/NBK493476/