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W4226312056 abstract "INTRODUCTION Psychotropic medications are known to be associated with certain side effects that can present as medical emergencies. These include neuroleptic malignant syndrome, serotonin syndrome, anticholinergic syndrome, dystonia, akathisia, etc. For these conditions, the etiological relationship of the side effect and the medical emergency is well established. In addition, the use of psychotropic medications is also associated with other side effects, which may mimic a physical illness [Table 1]. It is important to understand that for these side effects, at present, the data is available only in the form of association studies. Patients with these presentations may be encountered in emergency setting, other medical-surgical wards, and in various psychiatric setting. All these presentations require immediate attention. These side effects are mostly considered rare side effects, but when these occur and go unnoticed, then these could be fatal. The recognition of these side effects is usually not straightforward, as the association of these side effects with psychotropic medications require ruling out of other possible causes, and often the final conclusion is made after the acute crisis is resolved. The most common presentation of these side effects is altered sensorium, but depending on the side effect, the presentation can vary from difficulty in vision, to persistent erection, or nonspecific symptoms such as fever, fatigue, shortness of breath, palpitation, and constipation. Although most of these side effects are discussed in isolation in the literature, it is important to note that, many patients present with more than one of these rare side effects to the medical emergency. Hence, it is important to carry out a thorough evaluation to rule out all possible side effects and effectively manage the same. In most situations, detection of these side effects requires a high degree of clinical suspicion, taking a proper history, carrying a detailed physical examination, and ordering routine and certain specific investigations. An important issue encountered in such situations is to continue/discontinue the psychotropics, and to determine which psychotropics should be used to address the primary illness, should they be required the in future.Table 1: Medical emergencies associated with use of psychotropic medicationsThe present guidelines provide an overview for the evaluation of patients presenting with medical emergencies associated with psychotropic medications. Figure 1 presents the typical organ systems affected by psychotropic medications which lead to emergency treatment seeking. These guidelines are not a substitute to the clinical knowledge and every patient presenting with these features will require individualized assessment and management. Certain other medical emergencies where the association with psychotropic medications is much better established (such as acute dystonias, neuroleptic malignant syndrome, and serotonin syndrome) are discussed separately in another set of guidelines.Figure 1: Typical organ systems affected due to psychotropics which lead to treatment seeking in the emergencyINITIAL ASSESSMENT FOR ESTABLISHING THE ASSOCIATION AND GENERAL MEASURES FOR MANAGEMENT As discussed earlier, the diagnosis of psychotropics-associated medical emergencies (such as aspiration pneumonia, myocarditis, cardiomyopathy, pancreatitis, hepatic failure, etc) requires a high index of suspicion and awareness of the clinicians about the possibility. Whenever a patient with a psychiatric disorder presents with symptoms and signs akin to any medical illness, a possibility of the contribution of the ongoing psychotropic must be kept in mind. The most important aspect of evaluation includes establishing the relationship of the side effect with the ongoing psychotropic medication. A good history taking is of paramount importance in this regard. During the history taking the clinician should not only focus on anamnestic recall of facts but should also review all the available treatment charts (including the investigations and the ongoing medications) [Table 2]. The approach to patients with suspected medical emergency due to psychotropics is presented in Figure 2. While history taking due importance should be given to any recent change in medications, which could be either addition or removal of a medication. This is important from the drug interaction point of view, because, removal of an inhibitor can lead to increase in the serum levels of the ongoing psychotropic medication and resultant side effect. The definite association is usually established based on the temporal association, available evidence in the literature for such an association, response to the withdrawal of medication, and effect of rechallenge [Table 2]. Due importance should be given to the change in the doses of ongoing medications, as some of the side effects may be dose-related.Table 2: History taking in a patient presenting with a suspected side effects associated with the psychotropic medicationsFigure 2: Flowchart for general assessment and management of psychotropic medication induced side effectsAdditionally, a thorough physical examination should be carried out because it can provide important information about other side effects of the medications or other possible etiological factors responsible for or contributing to the clinical picture [Table 3]. For example, fever may provide hint for infections.Table 3: Physical examination and basic investigationsAll possible differential diagnosis in the form of other possible medical diagnosis associated with similar presentations and other medical emergencies (such as neuroleptic malignant syndrome, serotonin syndrome, anticholinergic syndrome) associated with the use of psychotropic medications must be considered. The third component of establishing the association is ordering or reviewing the investigations as these may provide information about the possible association of side effect/clinical presentation with the psychotropics or other possible explanations. In all patients, basic investigations must be carried out and any further investigations should be guided by the differential diagnoses considered, and advised by other clinicians. The general management measures should focus on the safety of the patient. Till the other possible cause is not established, it is better to stop/substitute the suspected ongoing psychotropic medication and other medications which may be contributing to the side effect [Table 4]. However, discontinuation/substitution of nonpsychotropic medications should be done in liaison with the concerned specialists, without destabilizing the medical condition. Maintenance of airways, breathing, and circulation is of paramount importance and appropriate measures must be taken to address the same.Table 4: General measures to be followed for managing side effects associated with psychotropicsThe subsequent sections deal with the specific medical emergencies, their assessment, and management. SEIZURES Seizure is a medical emergency which is associated with use of various psychotropics in the therapeutic doses, or in toxic doses. Seizures can also occur as part of withdrawal syndrome associated with benzodiazepine or rapid tapering of benzodiazepine or antiepileptic agents. Seizures in patients on psychotropic could also be a secondary manifestation of other side effects of psychotropics (e.g., seizure secondary to hyponatremia). In this section, we would limit ourselves to the discussion of seizures associated with the use of psychotropics in therapeutic doses. Antidepressants associated with a high risk of development of seizures include amoxapine, bupropion, clomipramine, maprotiline, and mianserin. Among the antipsychotics, the highest risk of seizure is reported with clozapine and chlorpromazine [Table 5]. In general, the risk of seizure is higher for second-generation antipsychotics (SGAs) compared to first-generation antipsychotics (FGAs). Among the SGAs, a higher risk is associated with clozapine, olanzapine and quetiapine.[3] Various risk factors have been reported to predispose to the development of seizures. Among the various risk factors [Table 6], the use of higher dose of psychotropics is reported to be one of the most important risk factor.Table 5: Psychotropics and seizures[1 2]Table 6: Risk factors for seizures[2 4]In terms of clinical manifestations, psychotropic-associated seizures may present as myoclonus, focal seizures, or generalized seizures. Accordingly, the patients may present to emergency with generalized tonic–clonic seizures or report of jerks. While taking history, besides the general issues as discussed earlier [Table 2] the clinician should focus on frequency, typology, and past history of seizures. In addition, while taking history, importance must be given to the doses of psychotropics used, any recent change in the doses, any addition or removal of any medication from the prescription, and other aspects as listed in Tables 2 and 7.Table 7: Specific issues in history taking and physical examination while evaluating the association of side effects with psychotropicsIn terms of differential diagnosis, other medical and neurological diseases should be considered and history taking and physical examination should focus on ruling out the same [Table 7]. Some of the common differential diagnosis can include meningitis, encephalitis due to any cause, other central nervous system infections, metabolic disturbances leading to seizures, stroke, and any kind of brain tumors. It is always advisable to rule out these possibilities and to consider neuroimaging in patients presenting with seizure. Other investigations such as cerebrospinal fluid analysis, autoimmune panel should be done in liaison with other specialists [Table 8].Table 8: Investigations specific for the suspected medication associated emergencyIn terms of management, besides the general measures [Table 4], the first step involves stopping/reducing the dose the offending agent. If a patient presents with status epilepticus then the first aim should be control the seizures and in such a situation loading doses of antiepileptics (phenytoin or levetiracetam) should be considered. In patients presenting with isolated seizures, if then reduction in the dose of the offending agent should be considered, without compromising the efficacy. If there is no alternative to the offending agent, then addition of antiepileptic medication should be considered [Table 9]. While choosing antiepileptic agents, issues of drug interactions and synergistic side effects, and the effect of the antiepileptic on the psychiatric disorder must be kept in mind.Table 9: Specific interventions for the suspected medication associated emergencyGLAUCOMA Acute angle-closure glaucoma can be an ophthalmological emergency associated with the use of some of the psychotropic medications. If not identified in time, the sustained raised intraocular pressure can lead to irreversible axonal damage within the retinal nerve fiber layer and the optic nerve, resulting in irreversible blindness.[16] The blockage of pupil by the psychotropics is usually mediated by adrenergic or anticholinergic properties, or by idiosyncratic nonpupillary blockage. The medications commonly implicated for the acute angle-closure glaucoma include the tricyclic antidepressants (TCAs) (associated with anticholinergic side effects), monoamine oxidase inhibitor antidepressants (MAOIs), phenothiazine, and other antipsychotics (associated with high anticholinergic side effects), benzodiazepines, topiramate, selective serotonin reuptake inhibitors (SSRIs) (paroxetine, citalopram, escitalopram, fluoxetine, fluvoxamine) and selective norepinephrine reuptake inhibitors (SNRIs). While starting various psychotropics the clinicians should be aware of the risk factors for angle-closure glaucoma [Table 10] and preferably medications with a lower risk of angle-closure glaucoma should be chosen.Table 10: Risk factors for acute angle-closure glaucoma[16 17 18]Acute angle-closure glaucoma can present with a sudden loss of vision, pain in the eye, redness of eyes, headache, blurring of vision, low vision, tunnel vision, seeing halos around the lights, and red eyes [Table 7]. In addition, the patients can also have systemic symptoms like nausea and vomiting.[16] The initial assessment should include a review of the symptoms. Investigations should focus on the assessment of intraocular pressure. Other investigations are determined by the severity of the symptoms [Table 8]. The management involves reduction in the doses or removal of the offending agent [Table 9]. PSYCHOTROPICS AND BLOOD DYSCRASIAS Various psychotropics have been shown to be associated with blood dyscrasias such as agranulocytosis, neutropenia, thrombocytopenia, anemia, eosinophilia, and thrombocythemia. Most of the data for this association is in the form of case reports/case series and retrospective studies. Among the various psychotropics, blood dyscrasias are more commonly reported with the use of clozapine. However, it is important to remember that these side effects are not limited to clozapine only, and others drugs [Table 11] can also cause blood dyscrasias. Different mechanisms have been reported to be responsible for these side effects.[19] The incidence of various hematological side effects with clozapine is reported to be: 0.38%–22% for agranulocytosis, neutropenia 0.9%–22%, eosinophilia 0.2%–61.7%, thrombocytopenia 4.8%–17.8%.[24] An important fact to note is that small sample size studies report higher incidence of blood dyscrasias with clozapine, and as the sample size increases the reported incidence reduces. A study from India reported the incidence of eosinophilia with clozapine to be 9.9%, thrombocytopenia to be 8.2%, neutropenia to be 0.6%, and anemia to be 2.2%.[24] The reported incidence rates for other psychotropics are relatively low.Table 11: Blood dyscrasias with various psychotropics[19 20 21 22 23]In terms of clinical manifestations, many of these drug-induced blood dyscrasias may be asymptomatic and are detected only on investigation. However, when symptomatic, these may present with vague or nonspecific clinical features [Table 11]. An important fact to note is that clozapine-associated eosinophilia may be associated with myocarditis, pancreatitis, colitis, toxic hepatitis, and pleural effusion. Clozapine-associated eosinophilia has also been reported to predict the development of neutropenia.[25] Clozapine-associated eosinophilia is also reported to be associated with pleural effusion, pancreatitis, myocarditis, colitis, hepatitis.[25] In terms of differential diagnosis, all possible causes of these abnormalities should be considered and ruled out on the basis of proper history, findings of physical examination, and investigations. There are no clear-cut guidelines for the management of neutropenia associated with other psychotropics other than clozapine. However, when these abnormalities are detected, it is better to stop the suspected offending agent, till the definite cause is not established. For clozapine-associated mild neutropenia (1000–1500/mL), stopping clozapine is not recommended. It is suggested that neutrophil count should be monitored thrice-weekly till the absolute neutrophil count (ANC) reaches more than 1500/mL. In case the patient presents with moderate neutropenia (500–1000/mL), then stopping of clozapine is recommended and daily monitoring of ANC count is to be done till ANC reaches till >1000/mL, and then monitor thrice-weekly till ANC >1500/mL and then weekly for 4 weeks. If the patient presents with severe neutropenia (<500/mL), then clozapine should be stopped, and granulocyte-colony stimulating factor should be started in consultation with hematologist and re-exposure to clozapine should be avoided in persons presenting with severe neutropenia.[26] Other measures involving management of hematological abnormalities should focus on the management of infections if present, prevent bleeding and blood loss and any kind of thrombosis. THROMBOEMBOLISM Many psychotropics have also been shown to be associated with the development of thromboembolism and this can manifest as venous thromboembolism or pulmonary thromboembolism. The available data suggest the association of thromboembolism with both FGAs and SGAs, with risk higher for the latter group of antipsychotics. The antipsychotics that have been linked to thromboembolism include chlorpromazine, haloperidol, prochlorperazine, clozapine (possibly higher risk than other antipsychotics), olanzapine, and risperidone.[2728] Although there is data in the form of case reports linking the association of antipsychotics such as quetiapine, large-scale data does not confirm the same.[2728] Aripiprazole has been in general not reported to be associated with increased risk of thromboembolism.[2728] Similarly, the use of antidepressants, i.e., TCAs, SSRIs, and other antidepressants have also been shown to be associated with increased risk of development of venous thromboembolism.[29] In this regard, it is important to be aware of the risk factors commonly associated with the development of venous thromboembolism and while prescribing antipsychotics, the clinicians should take these factors into consideration. These factors include immobilization due to any cause, receiving hormonal therapy, obesity, higher age, presence of varicose veins or venous insufficiency, dehydration, and thrombocytophilia.[27] The venous thromboembolism may present with leg pain or tenderness in the thigh region, leg swelling, or reddish discoloration of the skin, and raised temperature in the local area. The pulmonary thromboembolism manifests in the form of shortness of breath, tachypnea, tachycardia, and chest pain. In terms of management, the offending agent(s) should be stopped, and as with other drug-induced conditions other possible causes must be ruled out. Once diagnosed, thrombolysis with intravenous unfractionated heparin should be started with close monitoring of international normalized ratio (INR).[27-29] HYPONATREMIA Hyponatremia is one of the common electrolyte imbalance reported to be associated with the use of psychotropics of various classes. Among the various psychotropics hyponatremia is often reported in patients on antidepressants (mainly SSRIs), followed by carbamazepine, and antipsychotics. Hyponatremia has been rarely also noted with the use of benzodiazepines/anxiolytics. The incidence rates of hyponatremia with various psychotropics vary widely, mainly influenced by the sample size, and the cut-off value of sodium used to define hyponatremia. The incidence rates of hyponatremia with SSRIs vary from 0.06% to 40%,[30] with studies based on larger sample size reporting lower incidence rates. Studies which have compared various antidepressants suggest that the incidence rate of hyponatremia is lower with TCAs when compared to SSRIs. In terms of antipsychotics, there is data in the form of case reports or small observational studies which have reported the association of hyponatremia with risperidone, quetiapine, olanzapine, aripiprazole, and clozapine. In terms of FGAs hyponatremia has been reported to be associated with the use of phenothiazines. Mood stabilizers such as carbamazepine/oxcarbazepine, valproate, and lamotrigine have also been reported to be associated with hyponatremia with the incidence rate with carbamazepine in the range of 4.8% to 41.5% in small sample size studies. Among the various benzodiazepines and Z-category drugs, clonazepam, lorazepam, oxazepam, triazolam, alprazolam, temazepam, clorazepate, and zolpidem have also been shown to be associated with hyponatremia in various case reports. Among the various mechanisms, syndrome of inappropriate antidiuretic hormone secretion has been reported to be the most common mechanism responsible for psychotropic associated hyponatremia.[31] Many studies have evaluated the risk factors for the development of hyponatremia with psychotropics [Table 12]. Most of this literature is available in relation to antidepressants.Table 12: Risk factors for development of hyponatremia associated with psychotropics[31 32]The clinical presentation of hyponatremia is influenced by the severity of hyponatremia, i.e., mild (130–134 mmol/l), moderate (125–129 mmol/l) and severe (<125 mmol/l) hyponatremia. Often the hyponatremia is asymptomatic, but when symptomatic the patient may report of symptoms such as headache, confusion, muscle cramps, lethargy and severe agitation. Patients with serum sodium level <120 mmol/l can present with symptoms like seizures, delirium, stupor, Cheyne–Stokes breathing, diminished deep tendon reflexes, and coma. It is important to note that the initial manifestation of hyponatremia may be nonspecific and actually the manifestation may overlap with a manifestation of depression (e.g., fatigue, anorexia, confusion) or other side effects of the ongoing medications (e.g., gait disturbances, vomiting, fatigue). Hence, it is important to take a proper history and if there is worsening of these symptoms after the starting of the psychotropics, a possibility of hyponatremia should be considered. Whenever a patient on psychotropics, especially antidepressants, reports worsening of symptoms (e.g., fatigue, anorexia, confusion) within few days of starting the medications or presents to emergency or medical ward with seizures, other neurological signs, and symptoms or altered sensorium/stupor or coma, a possibility of hyponatremia should be considered. These patients need to undergo detail assessment, which include proper history taking, physical examination, and appropriate investigations [Tables 7 and 8]. The basic purpose of a detailed assessment should be establishing the diagnosis of psychotropic-related hyponatremia and ruling out all other possible causes [Table 13].Table 13: Differential diagnosis of psychotropic associated hyponatremiaThe treatment of hyponatremia is usually guided by the severity of the hyponatremia and the clinical manifestations. Whenever a medication is suspected to be the possible cause of hyponatremia, it should be stopped immediately. If the hyponatremia is of mild severity, stopping of the offending agent may be sufficient. However, if this does not lead to improvement of serum sodium levels to the normal range, then water restriction should be considered in addition to the stoppage of offending agent(s). However, if the hyponatremia is of moderate-to-severe nature, then in addition to the stoppage of the offending agent, the patient should be given hypertonic saline, in liaison with the physician [Table 9]. It is important to remember that a rapid correction of hyponatremia should be avoided, as this can lead to central pontine myelinolysis. In addition, while using hypertonic saline infusion, furosemide should be used to prevent the kidney from concentrating urine even in the presence of high levels of anti-diuretic hormone. If the hyponatremia does not improve with these measures, then vasopressin receptor antagonists (conivaptan/tolvaptan) may be considered in liaison with the physicians. The management of hyponatremia due to psychotropics is presented in Figure 3.Figure 3: Management of patient with hyponatremiaOnce the hyponatremia improves, rechallenge with the same agent is not recommended, if other alternative agents are available to manage the primary psychiatric illness. In fact, it is suggested that other medications from the same class should be avoided. It is suggested that if a patient has a history of hyponatremia with SSRIs/SNRIs or if the patient develops hyponatremia with a SSRIs/SNRIs, antidepressant-like bupropion, mirtazapine, milnacipran, which are considered to have lower potential to cause hyponatremia may be considered. However, for antipsychotics, the current level of data does not suggest that hyponatremia with one SGA pose risk for the development of hyponatremia with another SGA. Clozapine is reported to improve serum sodium levels and it is considered as an option for the management of primary illness in patients who develop hyponatremia with other antipsychotics. It is recommended that the serum sodium levels should be monitored while the patient is being challenged with a newer agent. It is of paramount importance that, the clinicians are able to identify the persons at high risk for the development of hyponatremia and they take appropriate measures to prevent the same. While starting psychotropics the clinicians should be aware about the risk factors for hyponatremia and should avoid medications with higher potential to cause hyponatremia if other options are available. Further, in persons at high risk of developing hyponatremia, the clinicians should psychoeducate the patient and their family members about the clinical manifestations of hyponatremia and what should be done in such a situation. In addition, the serum sodium should be monitored closely in these patients during the initial phase of treatment, especially when the doses of medications are being increased. The doses of the medications potentially to cause hyponatremia should be increased slowly and other medications which can cause/contribute to hyponatremia should be changed or stopped in liaison with a specialist, without comprising the management of the primary illness for which these agents were being used. CARDIAC SIDE EFFECTS The cardiac side effects of psychotropics include tachycardia, bradycardia, arrhythmias, QTc prolongation, coronary artery disease/myocardial infarction, atrioventricular block, ventricular extrasystole, ventricular bigeminy, ventricular systoles, hypotension, hypertension, myocarditis, cardiomyopathy, and pericarditis. Some of the antipsychotics are also known to have a direct depressant effect on the heart and can lead to sudden cardiac death.[3334] Some of the cardiac effects may be due to direct effect of the psychotropics on the heart; others may be an outcome of drug interactions or may be an outcome of the use of concomitant medications, which also have similar cardiac side effects. The cardiac manifestations may also be secondary to other side effects of psychotropics, for example, hyponatremia leading to arrhythmias.[33] However, it is important to remember that these side effects are not clinically significant in most of the patients, but in occasional patients, these can be life-threatening and fatal. Hence, there is a need to monitor the cardiac status of the patients on psychotropics, especially those who are at high risk for developing cardiovascular side effects [Table 14].[34] Another issue to remember is the fact that patients with various psychiatric illnesses have a higher rate of cardiac ailments and are also associated with poor outcome.[3334] Due to all these factors, all patients considered for starting of psychotropics, especially antipsychotics, may be considered for electrocardiography (ECG) and blood pressure evaluation.[3334]Table 14: Patients at high-risk of developing cardiovascular side effects of psychotropics (adapted)[34]Among the various cardiac side effects, those which have a higher risk of fatality include significant QTc prolongation leading to torsade de pointes, myocarditis, cardiomyopathy, and pericarditis. QTc PROLONGATION AND TORSADE DE POINTES Various psychotropics have been reported to carry varying risk of QTc prolongation and Torsade de pointes [Table 15]. However, it is important to note that for some of the psychotropics, the data is not available to estimate the appropriate risk of this side effect. The risk of QTc prolongation and Torsade de pointes increases with the increase in the doses of most of the psychotropics which are considered to have a higher risk. Some of the demographic and clinical factors have been reported to be associated with increased risk of QTc prolongation [Table 16]. These must be kept in mind while selecting psychotropics, and whenever possible, the medications with higher risk should be avoided, if there is an option to use medications with lower or no risk of QTc prolongation and Torsade de pointes. Psychotropic medications reported to be associated with sudden cardiac death include chlorpromazine, droperidol, haloperidol, levomepromazine, pimozide, thioridazine, clozapine, olanzapine, quetiapine, ziprasidone, zotepine, pimavanserine, risperidone, sulpiride, tricyclic antidepressants (amitriptyline), SSRIs.[36]Table 15: Risk of QTc prolongation with psychotropic medications (adapted)[35]Table 16: Risk factors for QTc prolongation and torsade de pointes[33 35]In majority of the patients, QTc prolongation is asymptomatic and is identified only when the ECG is being monitored. However, some of the patients may present with nonspecific symptoms like lightheadedness, with or without palpitations, syncope or presyncope, and sudden cardiac arrest. Depending on the severity of ventricular tachyarrhythmia, the patients may also present with hypotension. On investigations, the patients may show prolonged QTc along with or without other cardiac rhythm problems. A QTc interval of 420 (±20) ms is considered to be normal in a healthy person after puberty. As per the American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death QTc interval of >450 ms for men, and >460 ms for postpubertal women are considered to be abnormal.[37] In addition, the evaluation should include reviewing the whole prescription and looking for other medications which can prolong QTc interval, and evaluating the various serum electrolytes disturbances (i.e., looking hypokalemia, and hypomagnesemia). Magnesium sulfate can be used in patients in prolonged QT" @default.
W4226312056 created "2022-05-05" @default.
W4226312056 creator A5037986670 @default.
W4226312056 creator A5045394669 @default.
W4226312056 creator A5064026468 @default.
W4226312056 date "2022-01-01" @default.
W4226312056 modified "2023-09-25" @default.
W4226312056 title "Management of systemic medical emergencies associated with psychotropic medications" @default.
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