The case, published in BMC Psychiatry by a team led by Aditya Shrivastav of Datta Meghe Institute of Medical Sciences in India, is a striking real-world illustration of the nocebo effect — the dark twin of the placebo response, in which negative expectations about a treatment actively generate the very symptoms a patient fears. Where placebo heals through belief, nocebo harms through it. And in an era when anyone starting a medication can spend an evening scrolling through forums and horror stories about its side effects, researchers argue the phenomenon is quietly sabotaging mental health treatment on a massive scale.

The clinical picture the woman presented was genuinely alarming. She had been diagnosed with moderate major depressive disorder, and sertraline — a selective serotonin reuptake inhibitor, or SSRI — was a reasonable, guideline-consistent choice. But within two days of the first tablet, the cardiopulmonary storm began. Emergency physicians found sinus tachycardia, a racing but otherwise structurally normal heart rhythm, with no ischemic changes on the electrocardiogram to suggest the heart muscle was being starved of oxygen. Serial cardiac biomarkers, the proteins that spill into the bloodstream when heart tissue dies during a heart attack, remained stubbornly within normal limits. There was no clot, no arrhythmia crisis, no metabolic derangement to explain what she was feeling.

Then the imaging added a twist that kept the case from being dismissed. A transthoracic echocardiogram — an ultrasound of the beating heart — showed borderline left ventricular systolic function, with an ejection fraction of 51 percent, just under the conventional threshold of normal, accompanied by mild diffuse global hypokinesia, a subtle generalized weakening of the heart’s contraction. A brain MRI ruled out acute intracranial pathology. In other words, something real was measurable in her body, but nothing pointed to the acute cardiac catastrophe her symptoms seemed to announce. The team treated her supportively, and the symptoms gradually resolved — a pattern more consistent with a transient, expectation-driven physiological storm than with structural heart disease.

The detective work that followed is what elevates this from an oddity to a teaching case. When clinicians sat down with the patient for detailed psychiatric reassessment, a crucial piece of history emerged: before taking her first dose, she had immersed herself in online information about antidepressant adverse effects. And the symptoms she had read about — palpitations, chest tightness, breathlessness, dizziness — matched, with uncomfortable precision, the symptoms she then experienced. Her body had not simply malfunctioned. In a very real physiological sense, it had performed the script she had absorbed, translating anticipation of harm into autonomic arousal, hyperventilation, and cardiac symptoms indistinguishable from disease.

This is not metaphor; the nocebo effect has measurable biology. Expectation of a symptom activates the same neural circuitry that generates the symptom itself. Anticipatory anxiety drives sympathetic nervous system activation — adrenaline release, elevated heart rate, heightened interoceptive attention, the brain’s monitoring of internal bodily signals turned up to maximum gain. A person primed to detect palpitations will notice every benign flutter and interpret it as evidence of danger, which spikes anxiety further, which amplifies the sensation, in a self-reinforcing loop that can produce chest pain, hyperventilation, and genuine, measurable cardiovascular changes. The mind does not imagine the symptom. It manufactures it, through the same machinery that produces any other bodily experience.

What happened next is the part that should make every prescriber sit up. Rather than abandoning sertraline permanently — the fate of an estimated substantial fraction of patients who quit antidepressants in the first weeks because of early side effects — the team pursued a strategy of structured psychoeducation and expectation-targeted counselling. The patient was walked through what the medication actually does, what early effects are common and transient, and, critically, how expectation itself can generate symptoms. Then came the experiment that mattered: sertraline was reintroduced at a lower dose. This time, there was no recurrence of the cardiopulmonary symptoms. Same drug, same patient, same body — different expectations.

The five-week follow-up sealed the narrative. A repeat echocardiogram showed her left ventricular function had normalized entirely, with the ejection fraction rising to 58 percent. Her depression, measured on the 17-item Hamilton Depression Rating Scale, had fallen from 21 — firmly in the severe range — to 10, a substantial clinical improvement. The medication she had nearly lost to fear was, once fear was managed, doing exactly what it was prescribed to do. The authors are appropriately careful: a single case report cannot establish causality, and early genuine pharmacological effects of SSRIs cannot be completely excluded. But the absence of symptom recurrence after a psychoeducation-guided rechallenge is a powerful circumstantial fingerprint of an expectation-driven mechanism.

The broader implications reach well beyond one woman and one antidepressant. Adherence to psychiatric medication is a chronic, global problem, and the first two weeks of SSRI therapy are where most patients are lost — the window in which early side effects, real or expected, collide with a person who has not yet felt any benefit. The authors argue that recognition of nocebo phenomena, careful counselling, and proactive expectation management before the first tablet is swallowed could keep patients on effective treatment, spare emergency departments the cost of cascades of unnecessary cardiac workups, and prevent the premature discontinuation of medications that work. In an information environment where a search for any drug’s name surfaces its worst outcomes first, the prescription may increasingly need a companion: a conversation about what the internet has already told you, and what your own anticipating brain can do with it.

There is also a caution here for the rest of us, the patients rather than the prescribers. The case does not suggest symptoms are imaginary or that people should dismiss what their bodies tell them — this woman’s chest pain warranted a full emergency evaluation, and she received one, and that was the right call. What it suggests is that the mind is not a passive observer of pharmacology. It is a participant, sometimes a saboteur, capable of summoning the side effects it dreads most. The first dose of a medication, it turns out, is taken twice: once by the body, and once — often hours earlier, on a screen, in the dark — by the imagination. Only one of those doses comes with a dosage instruction.

Subject of Research: A nocebo effect case report in which expectation-driven cardiopulmonary symptoms after sertraline initiation mimicked acute cardiac pathology

Article Title: Nocebo-induced cardiopulmonary symptoms following sertraline initiation mimicking acute cardiac pathology: a case report

Article References: Shrivastav, A., Tivaskar, S., Luharia, A., & Mishra, G. (2026). Nocebo-induced cardiopulmonary symptoms following sertraline initiation mimicking acute cardiac pathology: a case report. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08525-9

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08525-9

Keywords: nocebo effect, sertraline, SSRI, placebo effect, major depressive disorder, cardiopulmonary symptoms, medication adherence, psychoeducation, treatment expectations, psychiatry, case report, antidepressants

Post COVID-19 condition is characterized by persistent and highly heterogeneous symptoms that most prominently affect the cardiopulmonary system, including breathlessness, fatigue, exercise intolerance, and dysautonomia. Despite years of research, the biological mechanisms driving these symptoms remain poorly understood. Previous work has documented immune dysregulation and epigenetic alterations in peripheral blood following acute infection, but the lung itself, the primary site of infection and immune activation, has remained largely unexplored at the epigenetic level in this patient group.

The research team, led by Frida Nikesjö, Kristofer Hedman, and Maria Lerm of Linköping University, recruited 13 patients who had experienced persistent symptoms affecting daily life for more than 12 weeks after COVID-19 in 2020 and 2021. Participants were referred to the Department of Clinical Physiology at Linköping University Hospital, where they provided blood and induced sputum samples at study inclusion and again one year later. Induced sputum has been validated as a reliable and biologically informative source of pulmonary immune cells for methylome analysis, allowing the researchers to isolate neutrophil-enriched and macrophage-enriched cell fractions from the lung environment.

At each visit, patients also completed validated questionnaires covering fatigue, quality of life, and dyspnea, and underwent objective physiological testing including symptom-limited cardiopulmonary exercise testing, dynamic spirometry, and single-breath carbon monoxide diffusion capacity measurement. To reduce dimensionality in this small cohort, the team combined questionnaire scores and physiological outcomes into a single symptom-physiology composite variable, categorizing each measure from normal to severely abnormal using clinical reference limits.

Genome-wide DNA methylation profiling was performed using the Illumina Infinium Methylation EPIC 850K array, with rigorous preprocessing that removed failed and cross-reactive probes, sex chromosome sites, and probes containing common single nucleotide polymorphisms. Cell type proportions were estimated using the EpiDISH reference-based deconvolution method, and longitudinal differential methylation was assessed within individuals using the limma framework, with patient identity as a blocking factor and estimated cell proportions, sex, age, body mass index, and smoking status included as covariates. Differentially methylated CpG sites required both an absolute mean methylation difference greater than 0.15 and a false discovery rate-adjusted p-value below 0.05.

The most striking finding was a sharp divergence between compartments. No significant longitudinal DNA methylation changes were detected in peripheral blood mononuclear cells, yet pronounced changes emerged in both lung-derived fractions. In the neutrophil-enriched fraction, the researchers identified 446 differentially methylated CpG sites between the two time points, 70 hypermethylated and 376 hypomethylated, mapping to 274 unique genes. Pathway enrichment analysis across 334 KEGG pathways revealed 43 significantly enriched processes, with Wnt signalling and circadian entrainment among the most prominent. Notably, 87 of the affected genes are known to interact with SARS-CoV-2 proteins according to the BioGRID database.

In the macrophage-enriched fraction, 34 differentially methylated CpG sites were identified, evenly split between hyper- and hypomethylation. Although these changes did not map significantly to any KEGG pathways, an overlap analysis revealed a single gene, KIAA0930, that was differentially methylated in both lung cell fractions. This gene has been implicated in hypoxia adaptation and lung cancer development, and protein interaction analyses place it at a network hub connected to the 14-3-3 protein family, part of the Reactome pathway describing how SARS-CoV-2 targets host intracellular and regulatory pathways. BioGRID further identifies a direct interaction between KIAA0930 and ORF3A, a viral accessory protein known to modulate immune responses and cellular stress pathways.

Crucially, the epigenetic changes were not merely molecular noise. Seventy differentially methylated CpG sites, mapping to 54 genes, showed changes in methylation that correlated with changes in the symptom-physiology composite variable over the year of follow-up. Seven participants improved symptomatically, three remained stable, and three worsened, and their methylation trajectories tracked these clinical courses. Protein interaction and Gene Ontology analyses of the correlated genes revealed significant enrichment in biological pathways related to cardiac function, including a module connected to the KEGG pathway for viral myocarditis, a finding that resonates with the cardiopulmonary symptoms, such as exercise intolerance and dysautonomia, that dominate the clinical picture of post COVID-19 condition.

The authors are careful to frame the study as exploratory and hypothesis-generating. The cohort of 13 patients is small, control samples from pre-pandemic healthy subjects were used only for contextual reference rather than direct statistical comparison, and the lung cell isolation approach yielded enriched rather than fully homogeneous fractions. Neutrophil proportions were higher at the first time point, and residual confounding from comorbidities or treatments cannot be excluded. Without longitudinally matched controls, age-related or time-dependent methylation changes unrelated to post COVID-19 condition cannot be fully ruled out, and no causal relationship between the epigenetic alterations and symptoms can be inferred from these data.

Nevertheless, the findings carry significant implications. The tissue-specific nature of the rewiring suggests that peripheral blood, the workhorse of most long COVID biomarker studies, may be an incomplete window into the disease process, and that neutrophil biology in particular may persist in an altered state well beyond acute infection, consistent with reports of immature and activated neutrophils, neutrophil extracellular trap formation, and epigenetic reprogramming of bone marrow progenitors after COVID-19. The enrichment of pathways involving AMPK signalling, circadian entrainment, and dopaminergic synapses also aligns intriguingly with recent clinical observations, including evidence that the AMPK activator metformin reduces the incidence of post COVID-19 condition. Larger longitudinal studies with matched controls and mechanistic validation will be needed to determine whether these pulmonary epigenetic signatures are drivers of persistent illness, scars of prior infection, or downstream echoes of physiological stress, but this first longitudinal map of the lung methylome in long COVID provides a clear and testable starting point.

Subject of Research: Longitudinal DNA methylation changes in lung immune cells of patients with post COVID-19 condition

Article Title: Longitudinal epigenetic rewiring in lung immune cells in patients with post COVID-19 condition

Article References: Nikesjö, F., Smiljanić, J., Sayyab, S., Martínez-Enguita, D., Gustafsson, M., Rosvall, M., Hedman, K., & Lerm, M. (2026). Longitudinal epigenetic rewiring in lung immune cells in patients with post COVID-19 condition. Epigenetics Communications, 6(1), Article 5. https://doi.org/10.1186/s43682-026-00046-6

Image Credits: AI Generated

DOI: 10.1186/s43682-026-00046-6

Keywords: post COVID-19 condition, long COVID, DNA methylation, epigenetics, lung immune cells, neutrophils, macrophages, induced sputum, SARS-CoV-2, cardiopulmonary symptoms, KIAA0930, viral myocarditis