Side effects are not a footnote to psychiatric treatment - they are often the center of it. In this edition of The Neuropsychiatry Brief, Justin Ray, MSN, PMHNP-BC of South Chesapeake Psychiatry explains why treatment-emergent adverse events drive real-world decisions, and what that means for medication management in Chesapeake, VA.
One of the things I do not often discuss publicly is that I have been speaking for the pharmaceutical industry for several years now. There are rules, there are boundaries, and there are certainly feelings about what can and should be said in those spaces. But one thing I have always believed is that if I am going to stand in front of other providers and discuss a medication, I need to actually believe in it. I have turned down opportunities on medications I did not believe in, and I have remained committed to the idea that the most useful thing we can give clinicians is not just efficacy data, but practical, honest guidance on how to navigate treatment-emergent adverse events in the real world.
That matters because treatment-emergent adverse events are not a side conversation. They are often the conversation. In psychiatry, medications do not fail only because they do not work. They also fail because people do not stay on them long enough to find out whether they would have worked. Adherence problems in depression treatment remain common, and patients frequently stop medications early because of unrealistic expectations, perceived lack of benefit, or adverse effects (LeBlanc et al., 2015; Solmi et al., 2020). A 2024 review similarly emphasized that antidepressant side effects are closely tied to nonadherence and discontinuation, which should not surprise any clinician who has ever watched a client abandon a potentially useful treatment after a miserable first week (Niarchou et al., 2024). That is why I have long felt that one of the most important jobs of the prescriber is not merely selecting the medication, but preparing the client for the experience of taking it.
This is where industry, clinical trials, and real-world practice can drift apart. Early registration studies are often done in highly structured environments with frequent visits, careful follow-up, and a level of clinical attention that does not remotely resemble ordinary outpatient practice. In depression trials, placebo response has been consistently large, with meta-analytic work showing placebo response rates in the range of roughly 35% to 40% in major depressive disorder trials and substantial placebo effects even in treatment-resistant depression studies (Jones et al., 2021; Rutherford et al., 2013). That should remind us that context matters. Attention matters. Monitoring matters. The therapeutic frame matters. If a person is seen repeatedly, assessed carefully, encouraged, and made to feel that improvement is both possible and expected, outcomes change. That is not fake medicine. That is medicine.
It also means that when a medication leaves the trial setting and enters ordinary practice, the clinician is now carrying much more of the burden than the study design did. The provider becomes the interpreter of side effects, the regulator of fear, the container for uncertainty, and often the reason the client either stays with the plan or abandons it. If a new medication rolls out and the first few clients report that they could not get out of bed for hours, felt unbearably restless, became nauseated, or had to pull off the road because they were too sedated to keep driving, it is not hard to see what happens next. The clinician begins to distrust the product. The client warns the next client. The medication may never get a fair chance, even if the adverse effects were transient and even if meaningful benefits would have emerged with a slightly different strategy.
To me, that is exactly why minimizing or sugarcoating treatment-emergent adverse events is such a mistake. Some people in commercial spaces seem tempted to smooth over those problems. I think that is the worst possible approach. Clients know when something feels bad. Providers know when they are being sold instead of educated. And once trust is lost, the medication often goes with it. A better approach is simple honesty: this medication may cause dizziness, nausea, sedation, activation, akathisia, or weight gain; some of these effects may be transient; some may not; here is how I think about them; here is how I dose around them; here is what I want you to watch for; and here is what we will do if it becomes too much. That type of conversation is not anti-medication. It is what gives the medication a real chance.
In one true clinical experience from my own practice, a client became so sedated that she had to pull over on the highway and sleep in her car on the way to work. That was not a hypothetical concern or a slide-deck caution. That was a real clinical experience. And if you are a provider and that is the kind of early feedback you are getting, are you going to think favorably of the medication? Is it going to continue to get a chance long enough for either the clinician or the client to see the positive effects that were observed in the studies? That is always the challenge. Sometimes the drug may be good. Sometimes the benefit may be real. But if the first contact with the medication is miserable enough, the treatment can die before it ever has a chance to show what it can do.
What makes that even more frustrating is when those real-world problems are minimized. I once had a representative respond to my concerns by suggesting that what I was seeing were merely “outliers” and that perhaps we needed to discuss the appropriate patient for the treatment. Really? That is precisely the kind of commercial reflex that loses clinicians. If enough clients are telling me they are too sedated to function, too nauseated to continue, or too activated to tolerate the medication, the answer is not to imply I somehow chose the wrong human beings. The answer is to acknowledge the reality, discuss mitigation strategies, and respect the fact that real-world treatment always reveals things the slide deck does not.
There is also a growing literature around expectation itself. Negative expectations can amplify adverse effects through nocebo mechanisms, while the framing of treatment can shape what people feel and report (Colloca & Miller, 2011; Pan et al., 2019). That does not mean we should manipulate clients or understate risk. It means that how we discuss risk matters. If every counseling session sounds like a warning label with a pulse, we should not be surprised when people become hypervigilant to every sensation. On the other hand, if we explain side effects clearly, normalize the possibility of transient discomfort, lay out a mitigation plan, and preserve the client’s autonomy, we can reduce panic without reducing honesty. That is a very different thing.
This is one reason I spend a great deal of time up front in education. In my experience, more time on the front end often means less chaos later. I have a vested interest in getting clients better faster and with fewer problems. That is true clinically, ethically, and practically. In a private practice model, or when managing high-acuity populations, inefficiency is not neutral. If I choose a medication, I want the client to understand why I chose it, what the data suggest, what I have personally seen with it, what could go wrong, and how we plan to respond if it does. I want them to know that I am not asking them to suffer blindly in the name of compliance. I want them to know they retain the right to stop, call, pivot, and make decisions without shame.
That lesson was burned into me years ago. Earlier in my career, I would start someone on a selective serotonin reuptake inhibitor and see them back a month later only to find out they had been vomiting every day or having relentless diarrhea. I would ask why they kept taking it, and the answer was often some version of, “Because you told me to.” That answer hits differently once you realize how much authority clients hand over to us, whether we deserve it or not. The prescriber-client relationship is not just pharmacology. It is power. And if we do not explicitly release people from the guilt of disappointing us, some of them will continue a medication long after the cost has outweighed the benefit simply because they think that is what obedience looks like.
So now I say it differently. I tell them that we are partners. I tell them they are paying me for my advisement, not for dominion over their decisions. I give them the scientific data, then I give them my experience, and I am careful to note that those are not always the same thing. I tell them that some things may feel rough at first, but that there is a reason we are considering the medication anyway. I explain what I am hoping to gain. I explain what I am trying to avoid. I explain how we may use the medication a little differently than in a study in order to make it more tolerable in actual life. That sort of collaborative framing is very much in line with shared decision-making models, which have been linked to better antidepressant use and lower early dropout by improving trust, expectations, and engagement (Bauer et al., 2014; LeBlanc et al., 2015).
There is another uncomfortable truth here as well: our belief in a treatment matters. Placebo is powerful, and not just in clinical trials. I am not talking about tricking clients. I am talking about the reality that confidence, conviction, coherence, and therapeutic alliance influence outcomes. If I speak about a medication as though I understand it, have used it, know its pitfalls, and have a plan for them, that affects how the client receives the treatment. It affects whether they persist through the shaky beginning. It affects whether they interpret an early sensation as danger or as something expected and manageable. In depression trials, placebo effects are not trivial background noise; they are large enough to complicate signal detection in both standard and treatment-resistant populations (Jones et al., 2021; Rutherford et al., 2013). In practice, that should remind us that the frame around treatment is not fluff. It is part of the intervention.
At the same time, we cannot let enthusiasm become denial. I have often liked brexpiprazole for adjunctive depression because, clinically, it can be very effective. But effectiveness does not erase tradeoffs. Weight gain with adjunctive brexpiprazole has been observed across pooled analyses, with short-term mean increases around 1.5 kg and longer-term gains in the range of roughly 3.4 to 3.8 kg, depending on the dataset and duration of follow-up (Kishi et al., 2019; Newcomer et al., 2019, 2023). That may be acceptable for some clients and unacceptable for others. The point is not to pretend the problem is not there. The point is to say it out loud, discuss who may tolerate that trade, who may not, and whether the clinical payoff is worth it in that particular life, in that particular body, at that particular moment.
I have joked before that in three decades of psychiatry I have never had a client, particularly a woman, ask me to help them gain weight. There is humor in that, but there is also a very real clinical principle underneath it. Our job is not to obsess over side effects in a way that scares clients away from treatment. Our job is to understand what actually matters to the person sitting in front of us. Some clients will tolerate nausea but not sedation. Some will tolerate sedation but not akathisia. Some would rather risk weight gain than stay depressed. Others would rather remain symptomatic than relive an experience of losing control over their body. Precision psychiatry is not just receptor pharmacology. It is understanding which burden this client is willing to carry in order to get where they want to go.
And that is why the conversation itself becomes treatment. The right medication with the wrong setup often fails. The wrong expectations can sabotage a good choice. The minimization of side effects destroys trust. The failure to explain transient phenomena leads to premature discontinuation. And the failure to respect autonomy turns treatment into compliance theater. By contrast, when clinicians acknowledge the reality of treatment-emergent adverse events, anticipate them, frame them honestly, mitigate them strategically, and align the plan with the client’s own goals, medications have a much better chance of surviving long enough to show us what they can actually do.
There is some evidence supporting that instinct. Early improvement during antidepressant treatment has repeatedly been associated with later response or remission, even though it is not destiny and non-improvers can still go on to do well (Belanger et al., 2022; de Vries et al., 2019). That matters because it reinforces the value of getting the opening phase right. If we can reduce unnecessary dropout, manage the transitional side effects intelligently, and keep clients engaged through the first few weeks, we improve the odds that they reach the part of treatment where genuine benefit becomes visible. Sometimes that means slowing the titration. Sometimes it means moving dosing to bedtime. Sometimes it means adding practical supports. Sometimes it simply means telling the truth well.
In the end, I do not think the most important psychiatric medications are the ones with the prettiest slide decks or the cleanest launch language. I think the most important ones are the ones that can survive contact with real life. Can the client actually take it? Can the clinician actually manage it? Can the side effects be anticipated, explained, and worked around? Can the client understand why the temporary discomfort might be worth enduring, while still knowing they are free to stop if the burden becomes too great? Those questions are not peripheral. They are central. If we want better outcomes, we need better medications, yes, but we also need better conversations.
Bauer, A. M., Parker, M. M., Schillinger, D., Katon, W., Adler, N., Adams, A. S., Moffet, H. H., & Karter, A. J. (2014). Associations between antidepressant adherence and shared decision-making, patient-provider trust, and communication among adults with diabetes: Diabetes Study of Northern California (DISTANCE). Journal of General Internal Medicine, 29(8), 1139–1147.
Belanger, H. G., Lee, C., Poliacoff, Z., Gupta, C. T., & Winsberg, M. (2023). Early response to antidepressant medications in adults with major depressive disorder: A naturalistic study and odds of remission at 14 weeks. Journal of Clinical Psychopharmacology, 43(1), 46–54.
Colloca, L., & Miller, F. G. (2011). The nocebo effect and its relevance for clinical practice. Psychosomatic Medicine, 73(7), 598–603.
de Vries, Y. A., Roest, A. M., Bos, E. H., Burgerhof, J. G. M., van Loo, H. M., & de Jonge, P. (2019). Predicting antidepressant response by monitoring early improvement of individual symptoms of depression: Individual patient data meta-analysis. British Journal of Psychiatry, 214(1), 4–10.
Jones, B. D. M., Razza, L. B., Weissman, C. R., Karbi, J., Vine, T., Mulsant, L. S., Brunoni, A. R., Husain, M. I., Mulsant, B. H., Blumberger, D. M., & Daskalakis, Z. J. (2021). Magnitude of the placebo response across treatment modalities used for treatment-resistant depression in adults: A systematic review and meta-analysis. JAMA Network Open, 4(9), e2125531.
Kishi, T., Sakuma, K., Nomura, I., Matsuda, Y., Mishima, K., & Iwata, N. (2019). Brexpiprazole as adjunctive treatment for major depressive disorder following treatment failure with at least one antidepressant in the current episode: A systematic review and meta-analysis. International Journal of Neuropsychopharmacology, 22(11), 698–709.
LeBlanc, A., Herrin, J., Williams, M. D., Inselman, J. W., Branda, M. E., Shah, N. D., Heim, E. M., Dick, S. R., Linzer, M., Boehm, D. H., Dall-Winther, K. M., Matthews, M. R., Yost, K. J., Shepel, K. K., & Montori, V. M. (2015). Shared decision making for antidepressants in primary care: A cluster randomized trial. JAMA Internal Medicine, 175(11), 1761–1770.
Newcomer, J. W., Eriksson, H., Zhang, P., Meehan, S. R., & Weiss, C. (2019). Changes in metabolic parameters and body weight in patients with major depressive disorder treated with adjunctive brexpiprazole: Pooled analysis of phase 3 clinical studies. Journal of Clinical Psychiatry, 80(6), 18m12680.
Newcomer, J. W., Meehan, S. R., Chen, D., Brubaker, M., & Weiss, C. (2023). Changes in metabolic parameters and body weight in patients with prediabetes treated with adjunctive brexpiprazole for major depressive disorder: Pooled analysis of short- and long-term clinical studies. Journal of Clinical Psychiatry, 84(5), 23m14786.
Niarchou, E., Roberts, L. H., & Naughton, B. D. (2024). What is the impact of antidepressant side effects on medication adherence among adult patients diagnosed with depressive disorder: A systematic review. Journal of Psychopharmacology, 38(2), 127–136.
Pan, Y., Kinitz, T., Stapic, M., & Nestoriuc, Y. (2019). Minimizing drug adverse events by informing about the nocebo effect: An experimental study. Frontiers in Psychiatry, 10, 504.
Rutherford, B. R., & Roose, S. P. (2013). A model of placebo response in antidepressant clinical trials. American Journal of Psychiatry, 170(7), 723–733.
Solmi, M., Miola, A., Croatto, G., Pigato, G. G., Favaro, A., Fornaro, M., Monaco, F., Carvalho, A. F., Stubbs, B., Veronese, N., & Correll, C. U. (2020). How can we improve antidepressant adherence in the management of depression? A targeted review and 10 clinical recommendations. Brazilian Journal of Psychiatry, 42(2), 189–202.
South Chesapeake Psychiatry provides psychiatric evaluation and ongoing medication management in Chesapeake, VA, offering both in-person visits and telepsychiatry across Hampton Roads and throughout Virginia.
Side effects should be discussed openly with your prescriber rather than managed by stopping medication on your own. A psychiatric nurse practitioner can adjust dose, timing, or agent. You can review side effects with South Chesapeake Psychiatry during an in-person or virtual visit.
Yes. Telehealth medication management lets patients across Hampton Roads review tolerability, dosing, and adverse events through secure virtual visits with an online psychiatrist in Virginia.
South Chesapeake Psychiatry provides expert psychiatric care and medication management in Chesapeake, VA, with in-person visits and secure telepsychiatry for patients across Hampton Roads and throughout Virginia. To request an appointment for psychiatric medication management, contact South Chesapeake Psychiatry today.
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This article is for educational purposes only and is not medical advice. Always consult a qualified clinician about your individual care.
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