Antidepressants and Activation Syndrome: Decades Without Definition

On a sunny summer afternoon many years ago, when I was a newly hatched nurse, I walked into a colleague’s office to deliver lab results and found her lying on top of her desk. Sprawled out like a business casual snow angel, she was staring at the ceiling, rocking slightly, her feet hanging off the edge. “So, uh,” I said hesitantly, “what are you doing, exactly? ” “I just started taking Zoloft,” she huffed. “And I feel like my body is turning inside out. ” My colleague was an experienced nurse practitioner in community mental health, always composed, and here she was, using one of our own medications and forced to lie on the furniture because she “just couldn’t stand to have my feet on the floor anymore. ” I delivered the lab results and made a hasty exit. When we met again days later, she was fine. At the time, I was puzzled, but these days, I can tell you what happened. She experienced activation syndrome. Identified as far back as the dawn of tricyclic antidepressants, activation syndrome was initially called jitteriness syndrome (Bennett et al., 1998; Lipinski et al., 1989; Pohl et al., 1986; Ramos et al., 1993; Weiss, 1988). Since then, I have seen it referred to as antidepressant-induced anxiety-jitteriness syndrome, excessive emotional arousal, behavioral toxicity, and other decidedly clunky terms. While it appears activation syndrome has become the preferred term in recent literature, no universal definition has ever been established, and attempts to improve a common definition have not amounted to much (Lopez-Castroman et al., 2020; Strawn et al., 2017; Tanaka et al., 2007). So, what is activation anxiety behavioral toxicity jitteriness syndrome? Well, frankly, no one knows. As caused by antidepressants, the working concept of activation syndrome is characterized by symptoms of increased anxiety, restlessness, agitation, irritability, excitability, disinhibition, impulsivity, insomnia, and/or general sense of being unwell, to name a few. The feedback loop of physical, mental, and emotional changes has never been fully distinguished, and heterogeneity in presentation is considerable (Bussing et al., 2015; Strawn et al., 2017). The pathophysiology is unknown, though genetic vulnerability and early serotoninergic changes may play roles (Celada et al., 2013; Luft et al., 2018). The widespread acknowledgement of activation syndrome appears to be built—somewhere between partially and completely—on anecdotal reports and clinical lore accumulating over decades of antidepressant use (Goodman, et al., 2007; Luft et al., 2018; Takeshima & Oka 2013). Something I find in the literature time and time again is essentially this: no one can tell you precisely what it is, but you’ll know it when you see it. If activation syndrome remains undefined, this undoubtedly affects our ability to better understand it through research. Without a reliable tool to use in identification, clinicians may struggle with separating activation syndrome from preexisting or worsening symptoms of the initially targeted disorder (Harada et al., 2008; Sinclair et al., 2009). Many studies have captured the hallmarks of activation syndrome without identifying them as such; countless controlled trials report side effects like restlessness or anxiety as a side effect without further investigation (Sinha et al., 2017). How many symptoms does one need before reliably diagnosing activation syndrome, and do we need to consider severity or duration or frequency of symptoms or any exclusion criteria? No one knows. A promising parent-rated scale for youths appeared in recent years but is not yet commonly used (Luft et al., 2018; Reid et al., 2015). The course of activation syndrome is also undefined. It begins in the first days or weeks of treatment; in my own patients, I find it usually starts within the first week after starting a new antidepressant. It seems to last a few days to two weeks (Lopez-Castroman et al., 2020; Luft et al., 2018; Sinclair et al., 2009). Its incidence is reported to be anywhere from 4% to 65% (Harada et al., 2008; Lopez-Castroman et al., 2020; Luft et al., 2018; Reid et al., 2010; Sinclair et al., 2009). Our patients certainly want to know if a medication has a 4% to 65% risk of weight gain, so one assumes they also want to be notified about equal chance of pacing the floors all night with a je ne sais quoi of uneasiness. To my mind, this is an important point to clarify, since a 4% occurrence might generate a few raised eyebrows at a conference somewhere, whereas a 65% occurrence would require hanging neon-lit signs in the lobby. A wide variety of factors seem to influence susceptibility, including dose, titration speed, enzymatic metabolism, diagnosis, and age, but diving into the literature unearths conflicting information (Amitai et al., 2015; Mills & Strawn, 2020; Murphy et al., 2008; Offidaniet al., 2013). Younger