Mental Health Meds & EMS: A Refresher
Introduction
Antidepressants are one of the most commonly prescribed medication classes in America. In fact, 2022 alone saw 6,768,106 million Americans be provided new antidepressant prescriptions (Chua et al., 2024). 2022 saw a 46 percent increase in antidepressant prescriptions (Chua et al., 2024). This trend continues to today.
While somewhat uncommon in comparison to other medication overdoses, antidepressant overdose and toxicity remains a growing threat to the public. In 2021 alone, antidepressants were primarily responsible for at least 5269 deaths (Drug Overdose Death Rates | National Institute on Drug Abuse, 2023). Antidepressants also played a significant role in polypharmacy overdoses and deaths. With the increased incidence of antidepressant use coupled with reduced education on its effects, antidepressant toxicity is becoming an important topic for EMS clinicians and healthcare workers in general to be educated on.
Antidepressants & Mechanism
In a significant portion of cases, depression is the result of a brain biochemistry disturbance. There are a plethora of different hormones and neurotransmitters that are associated with mood changes, but we will discuss the major, most studied ones in this article.
Serotonin is the main, major neurotransmitter that the most common antidepressant classes work on. It has a role in almost every single human emotion and mental process. For the purposes of discussing mental health medication, serotonin is primarily involved in feelings of well-being, anxiety, attention, reward and gratification, and sex drive. However, this is not an exhaustive list of serotonin’s roles.
Serotonin is produced in the brainstem and throughout the intestinal mucosa. It is converted into melatonin to regulate the sleep-wake cycle.
Serotonin is not only involved in mental health and mood regulation, but is also involved with motor function, gastrointestinal function, and even cardiac function. For instance, serotonin has positive inotropic and chronotropic effects which can prompt tachycardia in the presence of serotonin syndrome (Bamalan et al., 2023).
While low serotonin levels do play a role in depression, depression incidence is multifactorial and often involves a deficiency or imbalance of multiple important neurotransmitters. Depression is usually not as straightforward as being serotonin deficient.
Dopamine is another core neurotransmitter/hormone responsible for critical body functions. Dopamine plays a significant role in feelings of well-being and euphoria in addition to attention and gratification. Dopamine is also involved in neuromuscular function regulation. For instance, Parkinson’s disorder is actually a dopamine deficiency - and it’s treated with medications that essentially function as dopamine supplements! Other notable dopamine functions include renal function, urinary output, and vascular tone.
Dopamine plays a significant role in schizophrenia. Studies have shown that excess dopamine pathways are linked to schizophrenia incidence. High levels of dopamine in schizophrenic patients are linked to stronger positive symptoms such as hallucinations, delusions, and abnormal motor activity such as catatonia (Brisch et al., 2014).
Selective Serotonin Reuptake Inhibitors (SSRIs)
Common SSRIs: Zoloft (sertraline), Celexa (citaprolam), Paxil (paroxetine), Prozac (fluoxetine)
In 1988, the first SSRI - fluoxetine - was approved for use in the United States. Since then, SSRI use has ballooned to be the most commonly prescribed mental health medication class. Between 2016 and 2022, SSRIs were prescribed approximately 148,977,404 million times and constituted 67 percent of all antidepressant prescriptions in the United States (Chua et al., 2024b). A 2018 study found that fluoxetine was the 20th most commonly prescribed medication in the United States (Fuentes et al., 2018). SSRI use is widespread in adolescents, young adults, and older adults.
As the name suggests, SSRIs work by increasing the amount of serotonin that is reabsorbed by the body. It is theorized that increasing serotonin in a serotonin-deficient patient can reverse the effects of depression & anxiety.
SSRIs have a relatively good safety profile with minimal physical side effects compared to other mental health medications such as antipsychotics or MAOIs, making them the usual first-line option for uncomplicated depression or anxiety.
SSRIs can take up to 6 weeks to reach efficacy and require daily dosing to be effective (Chu & Wadhwa, 2023). Both psychiatrists and primary care providers commonly prescribe SSRIs due to their positive safety profile and relatively uncomplicated dosing regimens. Dosing is often increased at some point throughout the course of therapy. Patients can remain on SSRIs long-term - sometimes for decades - as long as they continue to yield benefits.
Serotonin syndrome is a rare but potentially life-threatening adverse effect of SSRI use. While SSRI use is the most common cause of serotonin syndrome, any combination of substances or conditions that leads to an excessive serotonin level can prompt serotonin syndrome. Serotonin syndrome is most commonly seen when patients are given multiple serotoninergic medications - for example, taking sertraline with valproic acid (commonly used for bipolar or seizure disorders) or even herbal supplements can prompt serotonin syndrome. It takes about 24 hours for serotonin syndrome to show symptoms following introduction of another serotonin-based medication.
Serotonin syndrome varies in severity, with the most mild patients presenting with tremor with others progressing into full-on nausea/vomiting, GI upset, persistent hypertonia, and unconsciousness. Serotonin syndrome is largely a clinical diagnosis made off of presentation findings and history - there’s no special hospital testing to find its presence.
Classic serotonin syndrome symptoms include clonus, hypertonia, hyperreflexia, GI upset, diaphoresis, fever, dilated pupils, AMS, eye tremors, and a return of the Babinski reflex (Simon et al, 2024). Symptoms are typically more pronounced and more easily assessed in the lower extremities (Simon et al, 2024).
Any patient with the presence of clonus, hypertonia, or hyperreflexia with a depression history or history of mental health medications should be strongly suspected for the presence of serotonin syndrome.
This is most commonly seen with overdose or when a patient is added to a new serotonergic medication.
There is no explicit prehospital treatment for serotonin syndrome. However, patients will benefit from symptom management, cardiac monitoring, and IV fluid resuscitation for dehydration (Simon et al, 2024).
Do not allow these patients to be written off as appropriate for BLS transport. These patients require intensive monitoring, including 12lead acquisition. Serotonin syndrome is often accompanied by general electrolyte derangement.
Consider the possibility of intentional overdose when treating patients that take mental health medications and are presenting with serotonin syndrome symptoms. Polypharmacy overdose may be at play rather than an isolated overdose of one medication.
St. John’s Wort
St. John’s Wort is a common herbal supplement that is used as an anxiolytic and antidepressant. It has become common in recent years within online mental health communities. Unlike most other herbal supplements, St. John’s Wort is known to be somewhat efficacious and is quite potent. It is available for purchase in a variety of stores, including on Amazon. It is available in a variety of formats including teas, foods, and pills. Concentrations available for sale vary.
St. John’s Wort primarily acts by increasing the amount of circulating dopamine, serotonin, and norepinephrine (Peterson & Nguyen, 2023). However, there is little research that fully explores its mechanism of action.
St. John’s Wort is metabolized through the liver via the P450 cytochrome system. As a result, patients with liver damage are at increased risk of toxicity due to delayed excretion. Patients with liver disorders are also at risk of depression. Ensure that you maintain a high index of suspicion for this when assessing patients.
Common uses for St. John’s Wort include generalized anxiety disorder, depression, and OCD. When stacked with other serotonergic medications, there is a severe risk for serotonin syndrome. Ensure that you conduct a thorough history on all patients taking mental health medications. Do not limit your questions regarding medications to typical prescribed medications; ask about herbal supplements and cultural foods too.
Selective Norepinephrine Reuptake Inhibitors (SNRIs)
Common SNRIs: Cymbalta (duloxetine), Effexor (venlafaxine)
Selective norepinephrine reuptake inhibitors (SNRIs) increase the amount of norepinephrine reabsorbed into circulation. Norepinephrine is commonly thought of as part of the “fight or flight” hormones (catecholamines) but also plays a significant role in general mood and attention. These medications are chemically similar to SSRIs but target a different neurotransmitter. The exact details of the relatively minor differences between SSRIs and SNRIs are not pertinent for this article.
Antipsychotics
Common antipsychotics: Haloperidol, droperidol, Abilify (aripiprazole)
As mentioned above, dopamine receptors and the level of circulating dopamine have a lot to do with manifestations of mental illness. Dopamine-centric conditions such as schizophrenia often present with hallucinations, delusions, abnormal motor activity, and excitability. Antipsychotics aim to manage these conditions, reduce specifically the positive signs of delusion conditions, and improve quality of life.
There are first and second-generation antipsychotics, with the first generation relying on dopamine blockading for its effects and the latter generation focusing on the general blockade of both serotonin and dopamine. Second-generation antipsychotics tend to have fewer side effects and are often the modern first-line treatment option for newly diagnosed patients.
Many of these medications can be given in weekly or even monthly injections for certain patient populations. Ensure that you interview about this.
There are several major complications that you should be aware of and maintain a high index of suspicion for when treating patients on antipsychotic therapy.
Neuroleptic malignant syndrome is a rare but life-threatening reaction to dopamine agents, such as antipsychotics. It is characterized by the onset of muscle rigidity, fever, and altered mental status following the introduction or untapered cessation of dopamine-blocking agents. Patients also often present with tachycardia, hypertension, new-onset tremors, and airway concerns. You should especially suspect this during the patient’s first month on any new antipsychotic medications.
Another consideration with dopamine medication use is medication-induced parkinsonism. Parkinson’s disorder is, put simply, a disorder of deficient dopamine resulting in poor muscle coordination. Because antipsychotics primarily work by blocking dopamine (D2) receptors, these medications can induce the same type of muscular dysfunction, shuffling gait, and bradykinesia seen in actual parkinsonism. This should be a consideration when assessing patients with long-term, progressive motor decline on antipsychotic therapy.
EMS does make use of antipsychotics in the field, including haloperidol and droperidol. These medications primarily work by inducing sedation in patients and helping reduce agitation. The risk of issues such as NMS and parkinsonism is low with the single doses that EMS uses, but is still present and should be considered.
Mental Health Medication Overdose
Tricyclic Antidepressants
Tricyclic antidepressants are a relatively old antidepressant class that has seen a resurgence in its use in recent years. These medications are touted as highly effective for depression symptom management but carry a dangerous risk profile when overdosed. Tricyclic antidepressants work primarily by inhibiting the reuptake of norepinephrine and serotonin. If we have excessive amounts of these hormones in the body, what do you think the effects will be?
Tricyclic antidepressant overdose results in symptoms similar to any other anticholinergic overdose. Overdose symptoms will onset rapidly and will have their full effects appear within 6 hours in most instances (Khalid & Waseem, 2023). Patients that have been asymptomatic over 6 hours since reported ingestion can usually be safely assumed to have ingested a nontoxic dose (Khalid & Waseem, 2023).
TCAs also function as sodium, potassium, and calcium channel blockers (Khalid & Waseem, 2023). Patients will often present with tachycardia, decreased gastric motility, fever and hyperthermia, dry mucosa, and cardiac arrhythmias (Khalid & Waseem, 2023). These patients may initially present with seizures; be sure to maintain a high index of suspicion for the possibility of overdose in any seizure patient. Control the seizures appropriately with benzodiazepines while working to diagnose and correct the underlying cause.
EMS standard care focuses on identifying the underlying condition, obtaining a 12lead EKG, assessing their electrolyte status through physical assessment, controlling hyperthermia as necessary, and fluid resuscitation. Because TCAs can cause severe metabolic acidosis, sodium bicarbonate is used. Sodium bicarbonate helps maintain a normal pH and correct the associated mortality from acidosis. You should especially be prepared to give bicarbonate in the presence of QRS widening, clinical findings of severe metabolic acidosis, and in seizing patients (Khalid & Waseem, 2023).
Monoamine Oxidase Inhibitor (MAOI)
Monoamine oxidase inhibitors (MAOIs) are another less-commonly prescribed antidepressant medication class. Like TCAs, they are especially effective at treating depression symptoms but have a dangerous safety profile. As discussed above, neurotransmitters and hormones like dopamine, norepinephrine, and epinephrine play significant roles in the regulation of emotions and attention. These are all monoamines.
The creation and circulation of monoamines is precipitated by the amino acid protein called tyramine. Tyramine plays an essential role in circulating catecholamines throughout the body. MAOIs stop the breakdown of tyramine as a means to increase circulating monoamines and thus alter mood.
Patients that are taking MAOIs must follow a strict tyramine-controlled diet. Adding excess tyramine to the diet can result in excess circulation of catecholamines and prompt hypertensive crisis. This primarily occurs through excess stimulation of alpha-1 adenergic receptors (Laban & Saadabadi, 2023). These patients can experience rapid decline and eventually, a CVA if the hypertensive crisis is not controlled.
Examples of tyramine-containing foods include pickled foods, aged or smoked meats, fish, raisins, and alcohol. These patients can never drink alcohol - no amount is safe.
Common symptoms of an MAOI overdose include soaring hypertension, agitation, encephalitis, tachycardia, seizures, hyperthermia, and tremors (Laban & Saadabadi, 2023). There are no particular antidotes available for MAOI overdose. Prehospital care focuses on supportive care, including managing seizures, correcting hyperthermia, providing fluid resuscitation, and identifying the emergency in the first place.
MAOIs cannot be combined with SSRIs for risk of serotonin syndrome. Patients need at least a 2 week waiting period between discontinuing SSRIs and beginning MAOIs, or vice versa. Patients that have a shortened waiting period between discontinuing and beginning a new medication should be investigated for the possibility of serotonin syndrome. MAOIs cannot be stacked with most other mental health medications. There are also significant herbal contraindications, including with St. John’s Wort.
Works Cited
Bamalan, O. A., Moore, M. J., & Khalili, Y. A. (2023, July 30). Physiology, serotonin. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK545168/
Bhatia, A., Lenchner, J. R., & Saadabadi, A. (2023, June 22). Biochemistry, dopamine receptors. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK538242/
Brisch, R., Saniotis, A., Wolf, R., Bielau, H., Bernstein, H., Steiner, J., Bogerts, B., Braun, K., Jankowski, Z., Kumaratilake, J., Henneberg, M., & Gos, T. (2014). The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue. Frontiers in Psychiatry, 5. https://doi.org/10.3389/fpsyt.2014.00047
Chu, A., & Wadhwa, R. (2023, May 1). Selective serotonin reuptake inhibitors. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK554406/
Chua, K., Volerman, A., Zhang, J., Hua, J., & Conti, R. M. (2024). Antidepressant dispensing to US adolescents and young adults: 2016–2022. Pediatrics, 153(3). https://doi.org/10.1542/peds.2023-064245
Drug overdose death rates | National Institute on Drug Abuse. (2023, September 25). National Institute on Drug Abuse. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
Fuentes, A., Pineda, M., & Venkata, K. (2018). Comprehension of top 200 prescribed drugs in the US as a resource for pharmacy teaching, training and practice. Pharmacy, 6(2), 43. https://doi.org/10.3390/pharmacy6020043
Khalid, M. M., & Waseem, M. (2023, July 17). Tricyclic antidepressant toxicity. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK430931/
