Management of Systemic Medical Emergencies Associated with Psychotropic Medications.

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 medications

Medical emergencies	Commonly implicated medications
Neurological
Seizures	Antipsychotics, antidepressants
Haematological
Blood dyscrasias: agranulocytosis, thrombocytopenia, anaemia	Antipsychotics, antidepressants, mood stabilisers, benzodiazepines
Thromboembolism	Antipsychotics, antidepressants
Metabolic and endocrine related
Hyponatremia	Antidepressants, antipsychotics, carbamazepine/oxcarbamazepine, valproate, lamotrigine, benzodiazepines
Hyperammonemia	Valproate, olanzapine
Diabetes ketoacidosis	Antipsychotics
Pulmonary
Aspiration pneumonia	Antipsychotics
Cardiac
QTc prolongation and other cardiac conduction abnormalities	Antipsychotics, antidepressants, lithium
Hypotension	Antipsychotics, antidepressants
Hypertension	Antipsychotics, antidepressants
Myocarditis	Antipsychotics
Cardiomyopathy	Antipsychotics
Pericarditis	Antipsychotics
Gastrointestinal and hepatic
Pancreatitis	Antipsychotics
Acute liver failure	Antipsychotics, antidepressants, mood stabilizers, benzodiazepines
Gastrointestinal bleeding	Antidepressants
Intestinal obstruction	Antipsychotics, antidepressants
Genitourinary
Priapism	Antipsychotics, antidepressants, buspirone, methylphenidate, atomoxetine
Urinary retention	Antidepressants, antipsychotics
Ophthalmological
Glaucoma	Antidepressants, antipsychotics
Dermatological
Steven Johnson syndrome, toxic epidermal necrolysis	Antidepressants, antipsychotics, carbamazepine, lamotrigine

The 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 emergency

INITIAL 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 medications

History

• Review the clinical features and try to look for features specific to various medical emergencies

• Review the current psychiatric history including suicidal behaviour

• Review the history of intake of psychotropics in terms of starting of various medications, recent change in doses

• Review the history of physical comorbidities which are considered to be risk factors for various psychotropic associated medical emergencies: Diabetes mellitus, hypertension, hypothyroidism, COPD, cardiac failure, head injury, stroke, cirrhosis of liver, malignancies

• Review the available treatment records: For past history of similar acute medical emergencies and their association with the psychotropics

• Review for other factors which could be contributing to the medical emergency

• To improve the detection of side effects, the physician should look for the anamnestic key factors listed below

• Dates of occurrence of psychiatric symptoms/seizures suspected of being side effects

• Dates of medication exposure, dechallenge, and rechallenge

• Previous psychiatric history

• Dates of worsening of existing comorbidities

• Other side effects of the same medications

• Plasma concentration measurements

• Dose of medication at which the side effects appeared

• Any recent change in dose just prior to onset of side effects

• Past history of exposure to medication and side effects at that time

• Addition of any other medication close to onset of side effects, which can also lead to similar side effects

• Compliance with medication

• Effect of nonadherence on side effect (improvement/worsening)

• If polypharmacy is given, dates of introduction or discontinuation of other drugs

• Evaluate concomitant medications and drug interactions

• Could the side effect be an outcome of drug interactions or concomitant use of other medications

Comorbidity may also contribute to similar manifestations

• Physical illnesses themselves can have recurrence or a patient can have new onset physical illness

Could the manifestation be secondary to another side effect

• For example, hyponatremia leading to seizures

Good history taking and review of treatment charts

• Emergence of any new metabolic abnormality which can explain the side effect(s)

• Worsening of primary illness, which can explain the emergence of side effect(s)

• Identify the probable factors which if not causative, may be contributory (concomitant medications, hospitalization, ICU stay, distress due to prolonged hospital stay, lack of sleep etc)

Factors determining causal relationships between medications and the possible side-effects

• Temporal relationship between the drug exposure and the side-effect

• Definitive pharmacological or phenomenological evidence of specific side-effects

• Presence or absence of alternative explanations for symptoms (e.g., disease, other drugs)

• Response to withdrawal of drug

• Effect of rechallenge with the same drug

• The diagnosis of a side effect being related to a medication should always be provisional-diagnosis is always confirmed after the resolution of the syndrome

• The most useful complementary examination for side effects investigation is generally the monitoring of plasma concentrations of suspected medications

• Use Naranjo’s scale/WHO UMC scales to grade the association

COPD – Chronic obstructive pulmonary disease; ICU – Intensive care unit; UMC – Uppsala Monitoring Centre

Figure 2

Flowchart for general assessment and management of psychotropic medication induced side effects

Additionally, 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 investigations

Physical examination

• Vitals: heart rate, blood pressure, respiratory rate, temperature

• Examination: Chest examination, examination of cardiovascular system, examination of abdomen, and neurological examination to look for specific signs associated with the medical emergency

Mental status examination

• Assess for current severity of the psychiatric symptoms, association of symptoms (increase or decrease) with starting or change in the doses of medications, evaluate for delirium

Investigations (guided by the clinical presentation)

• Haemogram, absolute neutrophil count

• Renal function test

• Liver function test

• May provide information about the reduced clearance

• May also be important while considering selection of psychotropics and other medications

• Blood glucose levels, lipid profile

• Serum electrolytes

• Indicator of metabolic disturbance, can influence selection of antidepressants/antipsychotics/antiepileptics

• Neuroimaging

• Chest X-ray

• Electrocardiogram

• May be important for selecting the psychotropic medications (QTc), if these are to be used in patients receiving other medications

All 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 psychotropics

• Decide about the treatment setting: Outpatient, inpatient (psychiatry/medical-surgical ward), intensive care unit

• Review the whole prescription

• Stop the psychotropic considered to be associated with development of the particular medical emergency

• Look for all other possible modifiable contributing factors and decide about discontinuation/substitution in liaison with the concerned specialists, without destabilizing the medical condition

• Manage the airways, breathing, and circulation

• Monitor vitals

• Stop all the unnecessary medications

• Stop the suspected psychotropic(s)

The 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[12]

High risk	Intermediate risk	Low risk
Antidepressants  • Amoxapine  • Bupropion  • Clomipramine  • Maprotiline  • Mianserin  • Imipramine in higher doses	Amitriptyline Imipramine	SSRIs Trazadone Venlafaxine MAOI Mirtazapine
Antipsychotics  • Chlorpromazine (dose related)  • Clozapine (titration and dose related)	Haloperidol	Fluphenazine Trifluoperazine Risperidone Olanzapine Quetiapine

SSRIs – Selective Serotonin Reuptake Inhibitors; MAOI – Monoamine Oxidase Inhibitors

Table 6

Risk factors for seizures[24]

Patient related predisposingfactors associated with psychotropic associated seizures

• History of epilepsy (including febrile convulsions) in the patient and/or their family

• Presence of neurological abnormalities (brain injury, interrupted blood brain barrier), cerebral atherosclerosis

• Preexisting EEG alterations

• Presence of general physical illnesses (e.g., malignant hypertension leading to hypertensive encephalopathy)

• HIV/AIDS

• CNS infection

• Preexisting EEG alterations

• Elderly age group

• Reduced drug clearance

• Impaired renal or hepatic functioning

• Substance abuse

• Alcohol abuse

Drug related predisposingfactors associated with psychotropic associated seizures

• Polypharmacy

• Higher doses

• Rapid titration

• Abrupt withdrawal

• Abrupt dose changes

• Prolonged treatment

• High serum levels

EEG – Electroencephalogram; CNS – Central nervous system

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 psychotropics

Side effects	Historyand clinical presentation	Physical examination
Seizures	• Seizures: Frequency, typology, past history	• Evaluate for neurological deficits
	• Medication adherence	• Evaluate for signs of meningitis
	• All medications taken: Prescription and over the counter	• Look for other features of drug toxicity, neuroleptic malignant syndrome, anticholinergic syndrome
	• Use of substances, including recent abstinence or intoxication
	• Can the seizure be attributed to the withdrawal or intoxication of the ongoing medication
	• Any recent suicidal behaviour
	• Evaluate the relationship of seizure with change in the
	• Complications arising due to the illness per se
	• Changes in the metabolic profile
	• Intake of other medications with higher risk of seizures
Glaucoma	• Severe headache	• Size of the pupil (mid-size)
	• Nausea	• Slit lamp examination
	• Vomiting	• Check the IOP
	• Pain the eyes	• Gonioscopy
	• Blurring of vision
	• Redness in eyes
	• Halos around the lights
Neutropenia	• Fever, chills, or sweating	• Evaluate for fever
	• Features of infection: Sore throat, cough or shortness of breath, burning micturation, loose motion	• Look for signs and symptoms of infection
		• Look for other conditions which can cause neutropenia
Agranulocytopenia	• Fever, chills, or sweating	• Evaluate for fever
	• Fatigue	• Look for signs and symptoms of infection
	• Bleeding gums	• Look for other conditions which can causeagranulocytopenia
	• Features of infection: Sore throat, cough or shortness of breath, burning micturation, loose motion
Eosinophilia	• Rash	• Evaluate for respiratory symptoms, features of pancreatitis, myocarditis, colitis, hepatitis
	• Itching	• Evaluate for features of DRESS syndrome
	• Diarrhoea	• Look for other conditions which can cause eosinophilia
	• Respiratory symptoms
	• Pain abdomen
	• Skin lesion DRESS
Thrombocytopenia	• Bleeding gum	• Look for all signs and symptoms of bleeding
	• Petechiae	• Look for other conditions which can cause • Thrombocytopenia
	• Purpura
	• Blood in urine/stool
Thrombocytosis	• Headache	• Look for other conditions which can cause Thrombocytosis
	• Dizziness
	• Chest pain
	• Fatigue and/or weakness
	• Numbness or tingling of the hands and feet
Venous thromboembolism	• Leg pain or tenderness in the thigh region	• Look for leg swelling, skin temperature, tenderness
	• Leg swelling, or reddish discoloration of the skin, and raised temperature in the local area	• Respiratory symptoms
	• Pulmonary thromboembolism may manifest with shortness of breath, tachypnea, tachycardia and chest pain
Hyponatremia	• Headache	• Evaluate the sensorium
	• Confusion	• Look for features of delirium
	• Muscle cramps	• Deep tendon reflexed: Diminished
	• Lethargy	• Evidence of ataxia
	• Severe agitation	• Hydration status
	• Seizures	• Evidence for seizure
	• Delirium
	• Stupor
	• Chenyne stokes breathing
	• Coma
Hyperammonemia[56]	• Nonspecific symptoms: Acute onset lethargy, headache, dizziness, tiredness	• Detailed neurological examination
	• Gastrointestinal symptoms: Nausea, vomiting, constipation, loss of appetite	• Assess the level of sensorium
	• Neurological symptoms: Tremor, myoclonus, extrapyramidal symptoms, parkinsonism, ataxia, adiadochokinesia along with asterixis, slurred/illogical/bizarre speech, blurred vision, focal neurological deficits, seizures
	• Behavioural symptoms: Feeling slowed, sleep related issues (drowsiness, sedation, hypersomnia), altered mental state examination findings (such as decreased alertness, confusion, unconsciousness, obtundation, disorientation, forgetfulness, catatonia, irritability, psychomotor agitation)
	• Coma
Diabetic ketoacidosis	• History of recent weight changes (gain/loss), polyuria, polydipsia, Polyphagia	• Fruity breath
	• Weakness	• Assess the level of sensorium
	• Fruity breath	• Hydration status
	• Nausea
	• Vomiting with coffee-ground content
	• Dehydration
	• Altered sensorium
Aspiration pneumonia	• Cough with or without expectoration	• Fever or hypothermia
	• Difficulty in breathing	• Tachycardia
	• Fever	• Tachypnea
	• Fatigue	• Dullness to chest percussion in the areas of consolidation
	• Nausea	• Pleural rub
	• Vomiting	• Hypotension
	• Diarrhoea	• Altered sensorium or delirium
	• Respiratory failure	• Bad breath
QTc prolongation	• Light headedness	• Monitor the vitals
	• Palpitation	• Manage the airways
	• Syncope	• Features of dehydration
Hypotension	• Dizziness	• Assess vitals
	• Light-headedness	• Manage the airways
	• Headache	• Features of dehydration
	• Visual disturbance	• Assess for postural fall
	• Generalized weakness
Hypertension	• Headaches especially in the early morning	• Assess vitals
	• Epistaxis	• Assess blood pressure
	• Visual disturbances
	• Buzzing sound in the ears
	• Nausea
	• Vomiting
	• Anxiety
	• Chest pain
	• Fatigue
	• Confusion
Myocarditis	• Fever	• Assess vitals
	• Flu like symptoms	• Manage the airways
	• Nausea	• Assess blood pressure
	• Dizziness	• Detailed cardiovascular and respiratory evaluation
	• Tachycardia
	• Tachypnea
	• Chest discomfort
	• Hypotension
Cardiomyopathy	• Increasing breathlessness (most common symptom)	• Assess vitals
	• Orthopnoea	• Manage the airways
	• Paroxysmal nocturnal dyspnoea	• Assess blood pressure
	• Tachycardia	• Detailed cardiovascular and respiratory evaluation
	• Palpitations	• Look for peripheral oedema
	• Chest pain	• Evidence of raised jugular venous pressure
	• Fatigue
Pericarditis	• Flu-like symptoms	• Assess vitals
	• Fever	• Manage the airways
	• Tachycardia	• Assess blood pressure
	• Diarrhea	• Detailed cardiovascular and respiratory evaluation
	• Gastrointestinal symptoms
	• Chest pain
	• Shortness of breath
	• Dyspnea
Drug induced liver injury	• History: Concomitant medication intake	• Features of jaundice
	• Exposure to toxins	• Sweet or musty breath odour
	• Use of alcohol	• Other features of liver failure: Ascites
	• Fatigue	• Altered sensorium or delirium
	• Malaise
	• Loss of appetite
	• Epigastric discomfort
	• Pain in the right hypochondria
	• Jaundice
	• Itching
	• Arthralgia
	• Abdominal swelling
	• Nausea
	• Vomiting
	•Altered sensorium
Upper gastrointestinal bleeding[78]	• Concomitant medication intake: Aspirin, clopidogrel, warfarin	• Features of anaemia
	• Past history of upper gastrointestinal bleed	• Look for bruises
	• Bleeding for any other site	• Any other signs of bleeding
	• History of smoking, alcohol intake
	• Pain in the abdomen
	• Hematemesis
Intestinal obstruction-paralytic ileus	• Review history of use of other medications which can cause constipation	• Abdominal examination: Abdominal distension, tenderness, reduced or absent bowel sounds
	• Last passage of stool	• Vitals: Hypotension, tachypnoea, tachycardia, fever
	• Passage of flatus	• Features of septic shock
	• Constipation
	• Pain abdomen
	• Vomiting
Pancreatitis[9]	• Pain abdomen (epigastric pain, radiating to back)	• Abdominal examination-tenderness, muscle guarding
	• Fever, tachycardia	• Evidence of jaundice
	• Concomitant use of medications: Statins, steroids, NSAIDs, angiotensin converting enzyme inhibitor enzyme, retroviral therapy, etc.	• Respiratory distress
	• Substance abuse: Alcohol, cannabis, cocaine, opioids	• Altered sensorium
	• Rule out other causes like gall stones, hypertriglyceridemia, hypocalcemia, trauma, recent ERCP intervention, autoimmune causes
Priapism[1011]	• Duration of erection	• Proper examination of genitalia, perineum, and abdomen
	• Level of pain	• Examine the penis (in ischemic priapism, the glans will be soft, but the corpora is fully rigid and tender)
	• History of priapism, prolonged painful erections in the past	• Look for any signs of trauma, malignancy
	• Ongoing medications
	• Use of erectorgenic medications in the recent past
	• Drug abuse-especially opioids
	• History of sickle cell anaemia or other hemoglobinopathies
	• History of hypercoagulable states
	• Trauma to the local area
Urinary retention[12]	• Duration of urinary retention	•General signs of infection: Inspection, palpation
	• Past history of urinary retention	• Local examination: Examination of genitilia, per-rectal examination, tenderness
	• Signs and symptoms of different urinary tract infections	• Percussion over the bladder
		• Neurological examination

IOP – Intraocular pressure; DRESS – Drug reaction with eosinophilia and systemic symptoms; NSAIDs – Nonsteroidal anti-inflammatory drugs; ERCP – Endoscopic retrograde cholangiopancreato-graphy

In 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 emergency

Medical condition	Specific investigations
Seizures	• EEG
	• Neuroimaging
	• Cerebrospinal fluid analysis: In cases where meningitis, and encephalitis are differential diagnosis
	• Serum levels of drugs if required
Glaucoma	• Slit lamp examination
	• Tonometry: To check the IOP
	• Gonioscopy
	• Ophthalmoscopy
	• Visual fields
	• Ultrasound biomicroscopy
Neutropenia	• Haemogram
	• Complete blood count
	• Blood film
	• Bone marrow biopsy
	• Other investigations guided by differential diagnosis and clinical manifestations (i.e., site of infection)
Agranulocytosis	• Haemogram
	• Complete blood count
	• Blood film
	• Bone marrow biopsy
	• Other investigations guided by differential diagnosis and clinical manifestations (i.e., site of infection)
Eosinophilia	• Haemogram
	• Complete blood count
	• Blood film
	• Bone marrow biopsy
	• Other investigations guided by differential diagnosis and clinical manifestations (i.e., site of infection)
	• Look for possible underlying conditions associated with use of medications presenting with eosinophilia: Pancreatitis, myocarditis, colitis, pleural effusion, hepatic failure
Thrombocytopenia	• Haemogram
	• Complete blood count
	• Ultrasound abdomen to look for size of spleen
	• Blood film
	• Bone marrow biopsy
	• Other investigations guided by differential diagnosis and clinical manifestations (i.e., site of infection, dengue fever)
Thrombocytosis	• Haemogram
	• Complete blood count
	• Blood film
	• Bone marrow biopsy
	• Other investigations guided by differential diagnosis and clinical manifestations (i.e., site of infection)
Venous thromboembolism	• Compression ultrasound/duplex ultrasonography
	• Magnetic resonance imaging
	• Plethysmography
	• Venography
	• INR
	• Compression stocking
	• If pulmonary embolism is suspected: Computed tomographic pulmonary angiography, ventilation-perfusion (V/Q) scan, pulmonary angiography, magnetic resonance imaging
Hyponatremia	• Serum sodium levels
	• Other serum electrolytes
	• Urinary sodium (>30 mEq/L indicates SIADH)
	• Urinary osmolality (>100 mEq/L indicates SIADH)
	• Electrocardiogram
	• Blood glucose levels, lipid profile, serum protein levels
	• Renal function tests, liver function test
	• Investigations to rule out other differential diagnosis
	• Neuroimaging: If central pontine myelinolysis is suspected
Hyperammonemic encephalopathy[5]	• Serum ammonia levels
	• EEG, MRI, CT
	• Serum glutamate levels
	• Serum carnitine levels
	• Investigations for evaluating the defect in urea cycle: OTC deficiency
Diabetic ketoacidosis[13]	• Hba1c
	• Urine ketones
	• Serum ketones
	• Effective serum osmolality (mOsm/kg)
	• Anion gap (mEq/L)
Aspiration pneumonia	• X-ray chest
	• Arterial blood gas analysis
	• Sputum for culture
	• Blood culture
	• Haemogram including the TLC and differential count
	• Other investigations like HRCT, bronchoscopy, thoracocentesis: Guided by differential diagnosis and severity
QTc prolongation	• ECG
	• Serum electrolytes (potassium, magnesium)
Hypotension	• ECG
	• Serum electrolytes (potassium, magnesium)
Hypertension	• ECG
	• Serum electrolytes (potassium, magnesium)
	• Evaluate for other causes of hypertension
	• Evaluate for complications of hypertension
Myocarditis[14]	• Haemogram (may show evidence of eosinophilia)
	• CRP
	• Troponin T and I
	• CK-MB
	• BNP
	• NT-pro-BNP
	• IL-6, and TNF-a levels
	• ECG
	• TTE
	• CMRI
Cardiomyopathy	• Transthoracic echocardiography: Dilated and thin-walled LV with systolic impairment
	• ECG changes
	• BNP
	• NT-pro-BNP
	• Cardiac MRI
Pericarditis	• ECG
	• CPK-MB levels
	• CRP levels
	• Troponin levels
	• Echocardiography
Drug induced liver injury	• Liver function test
	• Haemogram, absolute eosinophil count
	• Ultrasound abdomen
	• Other investigations based on differential diagnosis and complications: Viral markers, CT/MRI of the abdomen, Liver biopsy
Upper gastrointestinal bleeding	• Blood grouping
	• Upper gastrointestinal endoscopy
	• Bleeding and clotting time
Intestinal obstruction-paralytic ileus	• X-ray abdomen and pelvis
	• Ultrasound abdomen
Pancreatitis	• Ultrasound abdomen
	• Imaging: Computerised tomography of abdomen
	• Magnetic resonance cholangio-pancreatography
	• Serum amylase, lipase, alkaline phosphatase
	• Lipid profile
	• Serum calcium
	• Ig levels IgG4 levels
Priapism	• Coagulation profile
	• Corporal blood gas analysis (will aid in distinguishingarterial and ischemic priapism)
Urinary retention	• Renal function test, serum electrolytes, serum glucose levels
	• Urine-routine and microscopy
	• Ultrasound: Abdomen and pelvis
	• MRI brain and MRI spine (if neurological causes are considered)
	• Cystoscopy, cysto-urethroscopy
	• Urodynamic studies

EEG – Electroencephalogram; HRCT – High resolution computed tomography; SIADH – Syndrome of inappropriate antidiuretic hormone secretion; IOP – Intraocular pressure; INR – International normalised ratio; OTC – Ornithine transcarbamylase; ECG – Electrocardiogram; CRP – C-reactive protein; BNP – B-type natriuretic peptide; NT-pro-BNP – N-terminal fragment of pro-BNP; IL-6 – Interleukin-6; TNF-a – Tumor necrosis factor-a; TTE – Transthoracic echocardiography; CMRI – Cardiac magnetic resonance imaging; MRI – Magnetic resonance imaging; CT – Computed tomography; TLC – Total leucocyte count; CK-MB – Creatine kinase-myocardial band; Ig – Immunoglobulin; CPK – Creatine phosphokinase-myocardial band; LV – Left ventricle

In 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 emergency

Medical condition	Specific interventions	Prevention of the side effects
Psychotropic related seizures	• Step-1: Stopping the offending agent should be considered as the first option, if feasible	• Use of medications with lower risk of seizures
	• Step-2: If not feasible, reduction in dose, without compromising the efficacy should be considered	• Use of agents which have least impact on seizure threshold
	• Step-3: If there is no alternative to the offending agent, then addition of antiepileptic medication should be considered
Glaucoma	• Stop the offending agent	• Avoid use of medications with high anticholinergic and adrenergic agents in vulnerable groups
	• Medical therapy for acute glaucoma: Topical b-blocker, a2-agonist, prostaglandin analogues	• Regular ophthalmological review
	• Surgical intervention: Laser peripheral iridotomy, determined by the severity of symptoms
Neutropenia	• Stop the offending agent	• Regular monitoring of haemogram
	• Monitor the neutrophil count	• Making patient aware about the clinical features
	• Absolute neutrophil count
	• Continuation/discontinuation decided based on severity of neutropenia
	• Colony stimulating factor in patients with severe neutropenia
	• Manage the secondary infection
Agranulocytosis	• Stop the offending agent	• Making patient aware about the clinical features
	• Monitor the platelet count	• Making patient aware about the clinical features
	• Continuation/discontinuation decided based on severity of agranulocytosis
	• Colony stimulating factor in patients with severe neutropenia
	• Manage the secondary infection
Eosinophilia	• Stop the offending agent	• Making patient aware about the clinical features
	• Monitor the eosinophil count
	• Continuation/discontinuation decided based on severity of eosinophilia
	• Manage the secondary infection
	• Other measures depends on systemic involvement
Thrombocytopenia	• Stop the offending agent	• Making patient aware about the clinical features
	• Monitor the platelet count
	• Continuation/discontinuation decided based on severity of thrombocytopenia
Thrombocytosis	• Stop the offending agent	• Making patient aware about the clinical features
	• Monitor the platelet count
	• Continuation/discontinuation decided based on severity of thrombocytosis
Venous thromboembolism	• Stop the offending agent	• Monitor the INR
	• Serial compression ultrasound
	• Unfractionated IV heparin
Hyponatremia[15]	• Stop the offending agent(s)	• Making patient aware about the side effect and the clinical features
	• Monitor serum sodium levels daily till serum sodium levels normalize	• Use agents which have lower potential to cause hyponatremia to manage the primary psychiatric condition
	• Mild hyponatremia: Discontinuation of the drug and if this does not lead to an increment in the serum sodium level, water restriction (0.5-1 L/day) should be considered	• Monitor serum sodium levels in high risk groups, during the initial phase of treatment, especially when the doses are being increased
	• Moderate to severe: Discontinuation of the offending agent, water restriction (0.5-1 L/day), if neurological signs and symptoms are present then correction with hypertonic saline is indicated
	• 3% hypertonic saline administered at the rate of 1 mL/kg/h until clinical improvement and serum sodium increases by 4-6 mEq/L (the rate of correction of hyponatremia should not exceed a maximum of 10-12 mEq/L in 24 h in patients with severe hyponatremia
	• A bolus dose of hypertonic saline (100 mL of 3% saline) to be considered in patients with seizure or in coma
	• Avoid rapid correction of serum sodium as this can lead to central pontine myelinolysis
Hyperammonemic encephalopathy[5]	• Stop the implicated agent	• Low protein diet in patients with liver disease
	• Improve hydration	• Avoiding use of alcohol
	• Protein restriction
	• Monitor serum glucose levels and take appropriate measures
	• Lactulose/rifaximin/neomycin
	• L-carnitine
	• • Severe encephalopathy: Furosemide, acetaglutamide, mannitol to reduce cerebral edema
	• NCG if the patient has NAG synthetase deficiency
	• Dialysis if the serum ammonia level is between 300-500 mmol/L
Diabetic ketoacidosis	• Maintain hydration	• Using agents with lower potential to cause raised blood glucose levels
	• Maintain serum electrolyte levels	• Monitoring of serum glucose levels at regular intervals in patients on antipsychotics and other agents associated with weight gain
	• Insulin
	• Monitor serum glucose levels
Drug induced liver injury	• Remove the offending agent(s)	• Check for all the medications which the patient is taking
	• Use of liver protective agents	• Avoid alcohol
Aspiration pneumonia	• Remove the offending agent(s)	• Avoid polypharmacy
	• Oxygen support as per the requirement	• Encourage the patient to abstain from smoking and alcohol
	• Pulse oximetry	• If a patient has respiratory disease, than manage the same appropriately
	• Monitor the cardiac parameters	• Address the neurological comorbidities
	• IV assess and fluids as per the requirement	• Avoid malnutrition
	• Antibiotics	• Use the minimum effective doses of medications
	• Maintain hydration	• Avoid inappropriate and prolonged use of gastric acid secretion suppressors
	• Management of complications
QTc prolongation	• Removing/reducing the offending agent	• Baseline ECG and monitoring the ECG and potassium
	• Use of IV magnesium/potassium	• Slow escalation of the doses, especially of medications which have higher risk
	• Anti-arrhythmic agents	• Patient need to be psychoeducated to report immediately, if they have new symptoms in the form of palpitation, lightheadedness, syncope, etc.
	• Cardioversion	• Avoid medications which have high risk of QTc prolongation
Hypotension	• If the symptoms are mild, reduce the dose of the offending agent	• Avoid sudden change in the posture
	• If the symptoms are severe and life-threatening stop the offending agent	• Avoid physical activity, intake of alcohol, carbohydrate rich food, and exposure to heat
	• Abdominal binders	• Use abdominal binders
	• Compression leg stocking	• Compression stocking
	• Increase fluid intake	• Adequate fluid intake
Hypertension	• Stop the offending agent	• Low salt diet
		• Healthy diet
		• Regular physical exercises
		• Avoid smoking and alcohol
		• Adequate sleep
Myocarditis	• Stop the offending agent	• Baseline investigation and assessments: Troponin (T or I), CRP levels, ECG, echocardiography, heart rate, temperature, blood pressure
	• Stabilize the cardiac status	• Monitor daily: Fever, chest pain, dyspnoea, myalgia, headache, cough, diarrhoea, vomiting, etc.
	• Corticosteroids	• Monitor every 2 days: Pulse, blood pressure, respiratory rate, temperature
	• Diuretics, beta-adrenergic blockers	• Every 7 days: Troponin (T or I), CRP levels
	• ACE inhibitors
	• ARBs
Cardiomyopathy	• Stop the offending agent	• Monitor the cardiac status
	• Stabilize the cardiac status
	• Corticosteroids
	• Diuretics, beta-adrenergic blockers
	• ACE inhibitors
Pericarditis	• Stop the offending agent	• Monitor the cardiac status
	• Stabilize the cardiac status
Upper gastrointestinal bleeding (Andrade and Sharma, 2016; Stanley and Laine, 2019; Bixby et al., 2019)	• Remove the offending agent(s)	• Concomitant use of proton pump blocker
	• Review the concomitant medications and discontinue/substitutethe medication in liaison with the specialist	• Making the patient aware about the side effect
	• Endoscopy	• Weigh the risk and benefits of using antidepressants in high risk groups
	• Avoid unnecessary use of NSAIDs
Intestinal obstruction- paralytic ileus	• Stop the offending agent	• Encourage patients to monitor the bowel habits
	• Supportive management	• Encourage patients to consume high fibre diet, take adequate fluids and exercise regularly
	• In case of perforation: Surgical intervention may be required
Pancreatitis	• Remove the offending agent(s)	• Avoid using the same agent or agents reported to be associated with pancreatitis
	• Achieve haemodynamic stability
	• Antibiotics
Priapism (Hwang and Shah, 2020; Salonia et al., 2014)	• Remove the offending agent(s)	• Decrease the dose or change the offending agent
	• Step-1: Penile aspiration to decompress the corpora cavernosa; continue aspiration till fresh red blood is aspirated	• Change to an agent with low alpha-adrenergic antagonist activity
	• Step-2: If the symptoms persist than give phenylephrine by diluting it normal saline (100-500 mg/mL concentration) and administered in the dose of 1 ml every 3-5 min in the corpus cavernosa with a maximum dose of 1 mg over 1 h, with close monitoring of vitals
	• Step-3: Surgical intervention (penile shunt surgery)
Urinary retention	• Stop/reduce the dose of the offending agents	• Have an understanding about the receptor profile of various medication which the patient may be receiving and avoid drugs with high anticholinergic properties and adrenoreceptor agonists needs to be avoided in vulnerable patients
	• Immediate catheterization to relieve the retention	• Avoid polypharmacy with agents with high anticholinergic properties and adrenoreceptor agonists

INR – International normalised ratio; NCG – N-carbamylglutamate; NAG – N-acetylglutamate; ACE – Angiotensin-converting enzyme; ARBs – Angiotensin II receptor blockers; NSAIDs – Nonsteroidal anti-inflammatory drugs; ECG – Electrocardiogram; CRP – C-reactive protein

GLAUCOMA

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[161718]

• Race (Inuit, Asian and Hispanic are at highest risk)

• Age >60 years

• Female sex

• Narrow angle (of anterior chamber)

• Shallow anterior chamber depth

• Hyperopia

• Thin central part of cornea

• Small eye (nanophthalmos)

• Previous angle closure in fellow eye

• Family history of angle closure glaucoma

• Use of any substance that causes papillary dilatation/excitatory situations

• Medical comorbities: Diabetes, heart disease, high blood pressure and sickle cell anaemia

• History of trauma to the eye

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[1920212223]

Side effect	Implicated medications	Common clinical presentations
Agranulocytosis	• Chlorpromazine, prochlorperazine, promazine, fluphenazine, haloperidol, thioridazine, clozapine, olanzapine, quetiapine, risperidone, ziprasidone	• Fever
	• Tricyclic antidepressants (amitriptyline/nortriptyline, imipramine, desipramine, clomipramine), tranylcypromine, mirtazapine	• Sudden onset malaise
	• Carbamazepine	• Infection involving any part of the body
	• Chlordiazepoxide, diazepam
Neutropenia	• Chlorpromazine, prochlorperazine, promazine, fluphenazine, haloperidol, thioridazine, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, lurasidone	• Low grade fever
	• Tricyclic antidepressants (amitriptyline/nortriptyline, imipramine, desipramine, clomipramine, doxepine), tranylcypromine, citalopram, mirtazapine, nefazodone, venlafaxine, trazadone, venlafaxine	• Sore throat
	• Valproate	• Infection involving any part of the body
	• Clonazepam, lorazepam
Leucocytosis	• Haloperidol, fluphenazine, clozapine, risperidone, olanzapine	• Fever
	• Citalopram, trazadone, venlafaxine	• Infection involving any part of the body
	• Carbamazepine, lithium
Leucopenia	• Carbamazepine, gabapentin	• Fever
Anaemia (aplastic, haemolytic)	• Chlorpromazine, risperidone, clozapine, lurasidone	• Easy fatigability
	• Tranylcypromine, citalopram, sertraline, mirtazapine, nefazodone, trazadone, venlafaxine	• Low energy levels
	• Carbamazepine, lamotrigine, valproate	• Shortness of breath
	• Chlordiazepoxide, clonazepam, diazepam	• Dyspnoea on exertion
		• Tachycardia
		• Poor attention and concentration
		• Dizziness
		• Pale skin
		• Pallor
Eosinophilia	• Chlorpromazine, fluphenazine, clozapine	• Fever
	• Tricyclic antidepressants (amitriptyline/nortriptyline, imipramine, desipramine)	• Skin rash
	• Carbamazepine
Thrombocytopenia	• Chlorpromazine, prochlorperazine, promazine, fluphenazine, thioridazine, haloperidol, trifluoperazine, methotrimeprazine, clozapine, olanzapine, quetiapine, risperidone, lurasidone	• Fatigue
	• Tricyclic antidepressants (amitriptyline/nortriptyline, imipramine, desipramine, clomipramine), tranylcypromine, sertraline, mirtazapine	• Heavy menstrual flows
	• Carbamazepine, lamotrigine, valproate	• Blood in urine or stools
	• Chlordiazepoxide, clonazepam, diazepam	• Easy or excessive bruising (purpura)
		• Superficial skin bleeding (petechiae)
		• Prolonged bleeding from injury
		• Bleeding from different sources
Thrombocytosis	• Clozapine, lithium	• Headache
		• Dizziness
		• Weakness
		• Numbness or tingling of hands and feets
Lymphopenia	• Clozapine	• Infection involving any part of the body
Pancytopenia	• Fluphenazine	• Fever
	• Clomipramine, mirtazapine	• Infection involving any part of the body
	• Lamotrigine
	• Diazepam
Pure erythrocyte aplasia	• Carbamazepine, lamotrigine, valproate	• Influenced by the severity of anaemia
Impaired platelet aggregation	• Citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline	• Bleeding
	• Chlordiazepoxide, diazepam
Disseminated intravascular aggregation	• Fluoxetine	• Thromboembolism

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[3132]

• Demographic variables: Older age, female gender (for antidepressants)

• Physical characteristics: Low body weight, especially when the weight is <60 kg

• Concomitant medications: Diuretics, anticancer drugs, antihypertensives, antidepressants, anti-diabetics, anti-inflammatory drugs, and anti-epileptics, cytochrome 450 inhibitors, polypharmacy

• Past history: Past history of hyponatremia

• Co-morbid medical conditions: Diabetes mellitus, hypertension, hypothyroidism, COPD, cardiac failure, head injury, stroke, cirrhosis of liver, malignancies

• Baseline serum sodium levels: Low baseline levels (i.e., serum sodium levels <138 mmol/L)

• Environmental factors: Summer season

• Nature of psychiatry disorder: Early onset psychiatric illnesses, longer duration of psychiatric disorder, prolonged admission

• Dose of psychotropic: Inconclusive (antidepressants and antipsychotics); higher dose in case of carbamazepine

• Duration of treatment: During the initial part of treatment with psychotropics

COPD – Chronic obstructive pulmonary disease

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 hyponatremia

• Psychogenic polydipsia (especially in patients in whom antipsychotics are contributing agents)

• Other organ failure: Cardiac, renal, hepatic

• Dehydration due to any cause

• Pseudo-hyponatraemia due to hyperglycaemia, hypertriglyceridemia, hypoproteinemia

• Undiagnosed physical morbidities: Hypothyroidism, hypoadrenalism, SIADH due to hormone secreting tumors, central nervous system lesions

SIADH – Syndrome of inappropriate antidiuretic hormone secretion

The 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 hyponatremia

Once 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]

• Elderly

• Children and adolescents

• Patients with preexisting cardiovascular risk factors or cardiac disorders, including coronary artery disease, acute coronary syndrome, myocardial infarction, heart failure

• Patients receiving concurrent medications with potential cardiac effects

• Poor Cyp450 metabolizers

• Patients with history of ventricular arrhythmias or syncope

• Family history: Long QT syndrome, sudden death, diabetes mellitus, hypertension, dyslipidemia, obesity

• Polypharmacy

• Use of higher doses

• Electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia)

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]

High risk	Moderate risk	Low risk	No risk
Thioridazine*	Chlorpromazine*	Haloperidol*	Zuclopenthixol
Pimozide*	Risperidone	Fluphenazine	Paliperidone**
Levomepromazine	Clozapine**	Flupenthixol	Aripiprazole
Sertindole**	Sulpiride	Amisulpiride	Opipramol
Quetiapine**	Clomipramine	Zotepine	Paroxetine***
Risperidone**	Ziprasidone**	Olanzapine	Sertraline***
Amitriptyline***	Fluoxetine	Mirtazapine	Fluoxetine
Imipramine***		Trazadone	Reboxetine
Doxepin***		Mianserin	Duloxetine
Desipramine***		Venlafaxine**	Methylphenidate***
Nortriptyline***		Citalopram***	Atomoxetine***
Maprotiline		Escitalopram	Carbamazepine
Lithium**		Bupropion	Valproate
		Methadone*	Lamotrigine
		Levomethadone*

*Generally accepted elevated risk of TdP; **Rare case reports of TdP, possible but not adequately documented TdP risk; ***Weak association with TdP, unlikely at therapeutic doses, elevated TdP risk in the presence of congenital QT syndrome. TdP risk according to the Arizona Arizona’s Center for Education and Research on Therapeutics (Arizona CERT)

Table 16

Risk factors for QTc prolongation and torsade de pointes[3335]

• Female sex

• Elderly

• Congenital QT syndrome

• Childhood history of recurrent seizures or syncopal attacks

• History of dizziness, light headedness, palpitations

• Idiopathic long QT syndrome

• Electrolyte imbalance: Hypokalemia, hypomagnesaemia

• Underlying cardiac diseases: Myocardial hypertrophy, atrioventricular block, ischemic heart, bradycardia, congestive cardiac failure

• Substance abuse: Especially alcohol, cocaine

• Polypharmacy: Patients taking of multiple medications each of which prolongs QTc intervals (e.g., an antipsychotic, antidepressant, and antibiotic)

• Drug interactions which increase the dose of a medication with QTc effects

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 QTc interval, even in patients with normal serum magnesium levels.

The management of patients with prolonged QTc and torsades de pointes is usually guided by the symptoms and the hemodynamic stability. Patients, who are clinically unstable, may require the use of antiarrhymic medications, and electrical cardioversion/defibrillation.

The first step involves achieving hemodynamic stability by ensuring the general measures [Table 3]. The patients need to be closely monitored for the cardiac functioning. Depending on the severity of the QTc prolongation, the implicated agent has to be stopped (if the QTc is >500 ms) or the dose can be reduced and ECG needs to be monitoring. If the patient has associated hypokalemia and hypomagnesemia, then these must be corrected.

To prevent cardiac arrest and the development of prolonged QTc and torsade de pointes, it is important to do baseline ECG and monitoring the ECG and serum potassium levels. While using medications which have a higher risk of QTc prolongation, the doses should be increased slowly. The patient needs to be psychoeducated to report immediately, if they have new symptoms in the form of palpitation, lightheadedness, syncope, etc. In patients at high risk of cardiovascular side effects, it is better to avoid medications that have high risk of QTc prolongation.[3334]

Hypotension

Many psychotropics are known to cause hypotension, especially the orthostatic hypotension. Different authors have categorized the risk in different manner. A review of product descriptions reported variable risk with different psychotropics [Table 17].[38] The risk of hypotension is further increased when antipsychotics are combined with various antihypertensive medications, and other cardiac medications such as angiotensin II receptor blocker, nitrates, calcium channel blockers, diuretics, and a-adrenergic blockers. In addition, the risk of orthostatic hypotension increases in patients with various diseases associated with autonomic failure (i.e., diabetes mellitus, alcohol dependence, Parkinson’s disease, multiple system atrophy, and pure autonomic failure) or presence of dehydration.[39] The clinical manifestation of orthostatic hypotension can include dizziness, light-headedness, headache, visual disturbance, and generalized weakness. If these symptoms are not given due importance, orthostatic hypotension can lead to syncope (which can lead to further complications like fractures and hemorrhage), transient ischemic attack, stroke, myocardial infarction, and death.[39]

Table 17

Risk of hypotension adapted[38]

Very often (10% or more)	Often (1–<10%)	Occasional (0.1–<1%)	Rarely/very rarely (<0.1%)
• Amitriptyline	• Citalopram	• Citalopram	• Bupropion
• Tranylcypromine	• Imipramine	• Doxepine	• Trazadone
• Trimipramine	• Maprotiline	• Duloxetine	• Ziprasidone
• Chlorprothixene	• Mirtazapine	• Fluoxetine	• Carbamazepine
• Flupentixol	• Moclobemide nortriptyline	• Fluvoxamine	• Diazepam
• Levomepromazine	• Reboxetine	• Mianserin	• Flurazepam
• Olanzapine	• Trazadone	• Milnacipran	• Hydroxyzine
	• Venlafaxine	• Mirtazapine	• Nitrazepam
	• Modafinil	• Paroxetine	• Opipramol
	• Amisulpride	• Sertraline	• Levomethadone
	• Clozapine	• Venlafaxine	• Methadone
	• Fluphenazine	• Atomoxetine
	• Haloperidol	• Modafinil
	• Olanzapine	• Aripiprazole
	• Paliperidone	• Asenapine
	• Quetiapine	• Paliperidone
	• Sertindole	• Quetiapine
	• Thioridazine	• Risperidone
	• Zuclopenthixol	• Sertindole
	• Opipramol	• Sulpiride
	• Buprenorphine	• Ziprasidone
		• Carbamazepine
		• Buspirone
		• Diazepam
		• Lorazepam
		• Oxazepam
		• Pregabalin
		• Galantamine
		• Rivastigmine
		• Buprenorphine + Naloxone
		• Methadone
		• Naltrexone

The assessment of orthostatic hypotension includes recording of blood pressure appropriately. To consider that a person has orthostatic hypotension, there should be a minimum fall of 20 mm of Hg systolic blood pressure or 10 mm of Hg of diastolic blood pressure within 2–5 min of standing from siting position. The assessment should involve looking for other possible medications and physical health conditions which could be contributing to the postural fall. The management of orthostatic hypotension is influenced by the severity of the symptoms and the associated complications. If the symptoms are not severe, then initially the dose of the offending psychotropic agent can be reduced and the blood pressure can be monitored. In addition, the patients can be advised to use abdominal binders (starting from morning before getting up and removed at the bedtime) or leg compression stockings, and increase the fluid intake (1.25–2.5 L/day). However, if the symptoms are severe and disabling then the offending agent has to be stopped.[39]

While using psychotropics that are associated with a higher risk of postural hypotension, all the patients should be advised to avoid sudden change in the posture, especially while getting up from the bed in the morning.[39]

In addition, they should be informed that they should avoid physical activity, intake of alcohol, carbohydrate-rich food, and exposure to heat. They can be advised to use abdominal binders (starting from morning before getting up and removed at the bedtime).

Hypertension

Some of the psychotropics are also known to be associated with the development of hypertension. The review which included the product descriptions of various psychotropic agents reported the highest incidence of hypertension with atomoxetine [Table 18].[38] The rise in blood pressure could be an outcome of direct effect of the ongoing psychotropics or may be an outcome of the ongoing concomitant medications.[40] Hence, at the time of starting of various psychotropics that are associated with the development of hypertension, it is advisable to assess the blood pressure at the baseline.

Table 18

Risk of hypertension adapted[38]

Very often (10% or more)	Often (1–<10%)	Occasional (0.1–<1%)	Rarely/very rarely (<0.1%)
• Atomoxetine	• Bupropion	• Amitriptyline	• Duloxetine
	• Citalopram	• Carbamazepine	• Citalopram
	• Duloxetine	• Duloxetine	• Ziprasidone
	• Milnacipran	• Maprotiline
	• Reboxetine	• Nortriptyline
	• Tranylcypromine	• Paroxetine
	• Venlafaxine	• Sertraline
	• Methylphenidate	• Trazadone
	• Clozapine	• Bupropion
	• Paliperidone	• Modafinil
	• Risperidone	• Sulpiride
	• Galantamine	• Risperidone
	• Memantine	• Ziprasidone
	• Rivastigmine	• Carbamazepine
	• Buprenorphine + naloxone combination	• Buspirone
		• Pregabalin
		• Naltrexone
		• Varenicline

Patients with raised blood pressure may manifest with headaches especially in the early morning, bleeding from nose, visual disturbances, and buzzing in the ears. Patients with severe hypertension may additionally present with nausea, vomiting, anxiety, chest pain, and fatigue, and confusion. However, in the majority of the patients, high blood pressure is asymptomatic and is detected only on routine screening. Undetected high blood pressure may lead to angina, myocardial infarction, congestive cardiac failure, arrhythmias, sudden cardiac death, and renal failure.

Whenever rise in blood pressure is suspected, multiple readings must be recorded to confirm the presence of high blood pressure. In addition, efforts must be made to identify any other cause or contributing factor for hypertension. Whenever a patient on psychotropics presents with new-onset hypertension, the role of the psychotropic should also be considered. Whenever a psychotropic is suspected to be the offending agent, it should be stopped and blood pressure should be monitored.

MYOCARDITIS

Myocarditis is a rare side effect of antipsychotics, most commonly reported with the use of clozapine. It is characterized by inflammation of the myocardium. Besides clozapine, myocarditis has also been reported with use of quetiapine,[41] haloperidol and chlorpromazine,[42] amisulpiride, aripiprazole, asenapine, olanzapine, quetiapine, and risperidone. The reported incidence for myocarditis with clozapine is 0.015%–8.5%, and that for olanzapine is 0.002%, risperidone is 0.002%, and that for quetiapine is 0.006%.[14434445] In terms of geographical variation, higher incidence of clozapine-associated myocarditis has been reported in people from Australia.[144445]

Clozapine-associated myocarditis has maximum level of evidence, compared to myocarditis associated with other psychotropics and it is suggested to be due to immunoglobulin E–mediated hypersensitivity reaction.[44] It is usually seen during the initial part of the treatment (first 2–3 months) with clozapine in previously healthy adults, with some cases reported as late as 1 year.[144445] The dose range associated with myocarditis has varied from 50 to 600 mg/day with a median dose of 250 mg/day.[144445] Various risk factors associated with clozapine-associated myocarditis include rapid increase in dose, increasing age, concomitant use of sodium valproate, SSRIs, lithium, another SGA, obesity, higher body-mass index, and increased serum concentration of creatine kinase.[144445]

The clinical presentation of myocarditis could be variable and it may manifest with nonspecific symptoms such as fever, flu-like symptoms, nausea, and dizziness. Some of the patients may present with cardiac symptoms in the form of tachycardia, tachypnea, chest discomfort, and hypotension. The detailed examination may additionally reveal the presence of crepitations, additional heart sounds with gallop rhythm, pericardial rub, and raised jugular pressure. Some of the authors have proposed diagnostic criteria for clozapine-associated myocarditis. According to one of the criteria either the patient should have histopathological evidence of myocarditis on myocardial biopsy within 45 days of starting of clozapine or should have evidence of new signs of cardiac dysfunction (heart rate [HR] >100 bpm for 24 h, third heart sound, basal crepitations, peripheral edema) with or without fever along with the presence of at least 1 of the following abnormalities: Elevated Troponins T and I[ >2 times of upper limit of normal], ECG changes suggestive of myocarditis, evidence of heart failure on X-ray, elevated Creatine kinase-MB (CK-MB) (>2 times of upper limit of normal), radiographic evidence or left or right ventricular systolic dysfunction, MRI confirming myocarditis and ruling out other causes of myocarditis.

Investigations in a patient suspected to have myocarditis should include hemogram (may show evidence of eosinophilia), and other inflammatory markers, i.e., C-reactive protein (CRP), troponin T and I, CK-MB, B-type natriuretic peptide (BNP), N-terminal fragment of pro-BNP, interleukin-6 (inconsistently reported), and tumor necrosis factor-a (inconsistently reported), all of which may be increased. In addition, the patient may have nonspecific ECG abnormalities or arrhythmias. Other investigations should include transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMRI). The TTE may reveal regional or global left ventricular dysfunction with normal wall thickness, or the patient may show biventricular systolic dysfunction with normal wall thickness. CMRI can provide similar information as TTE, and additionally may provide evidence for scar and edema (inflammation) within the myocardial tissues and is considered to be more sensitive and specific for the diagnosis of myocarditis.[144445] CMRI is considered to be most useful for diagnosing clozapine-associated myocarditis. It is important to remember that endomyocardial biopsy is considered to be gold standard diagnostic tool for myocarditis, which may reveal evidence of eosinophilic inclusions and inflammatory cellular infiltrates with or without associated myocyte necrosis. However, it is usually not recommended in view of invasiveness.[14]

As the drug-induced myocarditis is a medical emergency, management involves immediate stoppage of the offending agent, and general measures [Table 4]. Specific treatments are instituted based on the severity of the cardiac symptoms and include use of corticosteroids, diuretics, beta-adrenergic blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers. All of these must be used under the supervision of a cardiologist or a physician. Among all these, beta-adrenergic blockers are known to improve the ventricular function, reduce the progression of cardiac failure, and increase chance of survival.[144445]

As clozapine is associated with myocarditis, in terms of prevention, it is recommended to carryout baseline thorough cardiac evaluation and investigations and monitor the same regularly [Table 9] for first 4 weeks of clozapine therapy to detect myocarditis at an early stage. The monitoring may be increased if the person manifests signs and symptoms suggestive of myocarditis, either on physical examination (i.e., pulse rate more than 120 bpm or an increase in HR by more than 30 bpm) or on investigations (rise in CRP levels of 50–100 mg/l or rise in Troponin levels 14]

CARDIOMYOPATHY

Cardiomyopathy involves structural abnormality of the left ventricle and has been reported with the use of clozapine, aripiprazole, olanzapine, quetiapine, and risperidone.[43] The reported incidence with various antipsychotics varies from 0.04% to 0.2%.[43] Maximum evidence is available for clozapine and as with myocarditis, the incidence rates are higher for people from Australia. A retrospective study estimated the incidence of cardiomyopathy to be 4.65% (6/129) in patients receiving clozapine and followed up for 11 years (0.42%/year.[46] Compared to myocarditis, cardiomyopathy is usually seen by 6–9 months of starting of clozapine, however, it is important to note that it can occur as early as 1 month and as late as 6 years.[4447]

In terms of clinical manifestations, cardiomyopathy associated with antipsychotics is mostly asymptomatic and most of the patients also do not have a previous history of cardiac ailment and any potential medical risk factors.[4447] Among the various risk factors, low ejection fraction is considered to be a risk factor for the development of cardiomyopathy.

If symptomatic, the clinical features of cardiomyopathy may include breathlessness (most common symptom), poor/decreased exercise tolerance, orthopnea, paroxysmal nocturnal dyspnea, tachycardia, palpitation, chest pain, and fatigue. Physical examination may reveal evidence of peripheral edema which may be increasing overtime, raised jugular venous pressure, systolic murmurs (due to mitral and/or tricuspid insufficiency), and coarse crackles at the base of the lungs.

Diagnosis is usually based on the presence of left ventricular insufficiency (ejection fraction <50% of normal) in the echocardiography. TTE may reveal dilated and thin-walled LV with systolic impairment. Other supportive evidence in favor of diagnosis includes nonspecific ECG changes (Q waves seen in myocardial infarction, left ventricular hypertrophy and strain seen in hypertension, etc.), increased serum concentrations of BNP and NT-proBNP. Cardiac MRI can be useful in distinguishing between other common causes of cardiomyopathy and can help in determining the prognosis.

The management involves stopping of the offending agent and taking care of general measures [Table 4]. This may be sufficient in improvement in the cardiac function, in patients with ejection fraction >25% at the time of diagnosis. Some of the patients may require supportive measures in the form of diuretics, beta-blockers, and ACE inhibitors, in liaison with a cardiologist.[4447]

PERICARDITIS

Pericarditis as a side effect of antipsychotics has been linked with the use of clozapine and quetiapine.[4849] It is documented as early as 7 days and as late as 7 years after starting of clozapine[49] and long-term use of quetiapine.[48] Some case reports suggest the development of constrictive pericarditis.[48] The clinical presentation of pericarditis includes mild flu-like symptoms, fever, tachycardia, gastrointestinal symptoms, chest pain, shortness of breath, and dyspnea. Investigation in patients suspected to have pericarditis should include ECG, creatine phosphokinase-MB levels, CRP levels, Troponin levels, and echocardiography. Patients with pericarditis may also have increased troponin I and/or T levels, eosinophilia, increased BNP and pro-BNP levels. The management involves discontinuation of the offending agent and addressing the cardiac decompensation.[49]

HYPERAMMONEMIC ENCEPHALOPATHY

Hyperammonemia (blood ammonia levels >45 mmol/L) is a potentially life-threatening condition, that has been reported to be associated with valproate/valproic acid, topiramate, lamotrigine, zonisamide, carbamazepine, phenytoin, risperidone, and olanzapine.[6505152] The drug most commonly implicated for hyperammonemic encephalopathy is valproate. The risk factors for valproate-associated hyperammonemic encephalopathy include urea cycle disorder, immature hepatic function, hereditary or dietary-induced carnitine deficiency, comorbid diseases (thyroid dysfunction), increased protein load, polypharmacy with more than one agent (concomitant use of other antiepileptics), and poor nutrition.[56] Available data suggest that the valproate associated hyperammonemic encephalopathy is not related to dose of valproate and duration of use of valproate.[5]

The clinical features of valproate-associated hyperammonemic encephalopathy can include nonspecific symptoms, or gastrointestinal symptoms, neurological symptoms, behavioral symptoms, sleep-related issues, and altered mental state examination and coma [Tables 7 and 8].[56]

The diagnosis of valproate/medication-associated hyperammonemic encephalopathy is usually based on ruling out the other possible causes of the clinical presentation, establishing high ammonia levels, and ruling out other possible causes of hyperammonemic encephalopathy. Patients with hyperammonemic encephalopathy can have normal liver function test results.[56]

Besides the routine investigations, if a patient is suspected to have hyperammonemic encephalopathy, serum ammonia levels must be done. Other investigations can include neuroimaging of the brain, investigations for evaluating the defects in urea cycle, serum glutamate levels, and serum carnitine levels [Table 8].[56]

The management involves stopping the offending agent, improving the hydration, restricting the intake of the proteins, monitoring of serum glucose levels, and use of agents like lactulose/rifaximin/neomycin. Some of the authors recommend the use of L-carnitine. Patients with severe hyperammonemic encephalopathy may require the use of furosemide, acetaglutamide, and mannitol to reduce cerebral edema. If the patient is found to have deficiency of N-acetylglutamate synthetase than N-carbamylglutamate may be used. Dialysis is recommended if the serum ammonia level is between 300 and 500 mmol/L [Table 9].[56]

DIABETIC KETOACIDOSIS

Diabetic ketoacidosis (DKA) is a rare side effect of SGAs, which is mostly reported in the form of case reports/case series. DKA has been reported with the use of clozapine, olanzapine, risperidone, quetiapine, and aripiprazole. Most commonly associated antipsychotics include olanzapine and clozapine. Some of the reports suggest association of DKA with the use of polypharmacy (i.e., use of more than one antipsychotic agent, with one of the medication being a SGAs). It is usually seen in initial phase of treatment with the particular antipsychotic, with the majority of cases seen during the initial 6 months of starting treatment. The risk factors for development of DKA with antipsychotics although reported inconsistently include middle age, male gender, unrecognized hyperglycemia or raised HbA1c levels, being overweight, and weight gain with the use of antipsychotic used.[1353] However, a nationwide nested case–control study reported a diagnosis of type-2 diabetes mellitus to be the only risk factor.[54] DKA may also be seen secondary to acute pancreatitis caused by various psychotropics such as valproate[55] and antidepressants.[56] The clinical presentation of DKA includes a history of recent weight gain or weight loss, polyuria, polydipsia, and polyphagia preceding the acute presentation. The acute presentation may include weakness, fruity breath, nausea, vomiting with coffee-ground content, dehydration, and altered sensorium.[53]

The investigations specific for DKA include HbA1c, estimation of urine and serum ketone bodies, assessing the effective serum osmolality (mOsm/kg) and anion gap (mEq/L). The management includes maintaining hydration, addressing the disturbances in the serum electrolyte levels, administration of insulin to normalize the serum glucose levels with 5–7 point monitoring [Table 9].

PSYCHOTROPICS AND PNEUMONIA

In the recent years, there is a considerable data to suggest the association of psychotropics, especially antipsychotics with the development of aspiration. The available data suggests that the risk ratio of developing aspiration pneumonia with antipsychotics is much higher when compared to those not on antipsychotics. A recent meta-analysis of the data from 14 studies suggests that the risk ratio of development of pneumonia is 1.69 (95% confidence interval [CI]: 1.34–2.15) with the FGAs and that for SGAs is 1.93 (95% CI: 1.55–2.41) when compared to no antipsychotics.[57] The studies which have compared the FGAs and SGAs suggest lack of significant difference between the two groups of antipsychotics.[57] The antipsychotics which have been commonly associated with the development of aspiration pneumonia include clozapine, risperidone, quetiapine, olanzapine, zotepine, and haloperidol.[575859] Although there is a lack of consensus, there is some data to suggest that aspiration pneumonia associated with the use of antipsychotics is associated with increased mortality among the elderly.[60] The various risk factors for the development of aspiration pneumonia include older age, male sex (recurrent pneumonia reported to be more common in females in one study), dementia, presence of chronic respiratory diseases like asthma and chronic obstructive pulmonary disease, tuberculosis within 1 year before baseline, dysphagia, smoking, cerebrovascular disease, polypharmacy (i.e., combined use of clozapine and another antipsychotic), concomitant use of benzodiazepines, valproic acid, systemic corticosteroids, and the early phase of treatment (with clozapine).[57616263] There is an inconsistent association of aspiration pneumonia with doses of antipsychotics, with some studies reporting clozapine to have a clear association with the development of recurrent aspiration pneumonia in a dose-dependent manner,[61] whereas other studies reporting no association of clozapine doses with risk of development of aspiration pneumonia.[63]

The increase risk of aspiration pneumonia with antipsychotics has also been seen in patients with bipolar disorder, and it has been reported to be dose-related, with higher doses of antipsychotics associated with a higher risk of aspiration pneumonia.[64] Interestingly, one of the studies which involved patients with bipolar disorder reported lithium to have a protective effect.[64]

Besides antipsychotics, benzodiazepines and benzodiazepine-related drugs like zopiclone and zolpidem have also been shown to be associated with increased risk of aspiration pneumonia due to sedation, especially in elderly with dementia.[6566] There is some data to suggest increased risk of pneumonia with antidepressants, valproate, carbamazepine, and pregabalin too, especially among the elderly.[66]

The risk factors for the development of aspiration pneumonia reported in the literature include older age, being underweight, and smoking habit.[67] It is also important to note that available literature in the general population suggests the association of aspiration pneumonia and/or community-acquired pneumonia with the use of alcohol, medication overdoses, seizures, stroke, head injury, esophageal conditions, neurological conditions like Parkinson’s Disease, myasthenia gravis, etc., protracted vomiting and lying in prolonged recumbent position, malnutrition, past history of community-acquired pneumonia, bronchial asthma, chronic bronchitis/chronic obstructive pulmonary disease, poor level of functioning, poor dental hygiene, use of immunosuppressive agents including oral steroids, and use of proton pump blockers.[68] These factors also must be taken into account while psychoeducating the patient and the family for the prevention of aspiration pneumonia in patients on psychotropics [Table 9].

The clinical picture of aspiration pneumonia is usually influenced by the severity of illness and the patient may present with mild respiratory symptoms (like cough with or without expectoration, difficulty in breathing, fever, fatigue, nausea, vomiting, diarrhea, fatigue, etc,) to the outpatient services or may land up in medical emergency or ward with severe symptoms like respiratory failure and septic shock. On examination, the findings may include clinical features of fever or hypothermia, tachycardia, tachypnea, dullness to chest percussion in the areas of consolidation, pleural rub, hypotension, altered sensorium, or delirium.[69] It is important to remember that the clinical presentation may have some overlap with other medical emergencies reported to be associated with the use of psychotropics. Hence, all these should be considered as differential diagnosis. In addition, other causes of pneumonia must be ruled out, before considering the possibility of psychotropic associated aspiration pneumonia.

The diagnosis of aspiration pneumonia is based on the physical examination findings and the findings in the chest X-ray. Other investigations in patients with aspiration pneumonia are guided by the severity of symptoms, establishing the causative agent and differential diagnosis [Table 8].

As with other conditions, offending agent should be immediately stopped. Depending on the severity of the symptoms, the patient needs to be admitted and the general measures [Table 4] need to be instituted. The selection of appropriate antibiotics must be done in liaison with the specialist. The supportive measures should include the oxygen support, maintaining an intravenous assess and fluids as per the requirement, monitoring of the cardiac parameters, and maintaining hydration [Table 9].

UPPER GASTROINTESTINAL BLEEDING

Antidepressants, especially SSRIs have been linked to increased risk of bleeding. The various sites of bleeding reported in the literature include ecchymosis, bleeding gums, subconjuctival bleeding, bleeding into joints, epistaxis, intracranial bleeding, increased vaginal bleeding, postpartum hemorrhage, epidural hematoma, upper gastrointestinal bleeding (UGIB), and increased risk of perioperative bleeding.[70] However, the bleeding which has received significant clinical attention is UGIB. A meta-analysis, which included 22 studies, of which 16 were case-control studies and 6 were cohort studies, with total sample size of more than 1,073,000 individuals, reported the odds ratio of UGIB with SSRIs to be 1.55 (95% CI: 1.35–1.78), compared to those not receiving SSRIs.[71] Another meta-analysis which included data of 1,255,073 participants (106,629 cases and 1,148,444 controls), from 31 case-control studies and 11 cohort studies reported the odd ratio for increased risk of UGIB with SSRIs to be 1.41 (95% CI: 1.27–1.57) in the case–control studies and 1.36 (95% CI: 1.12–1.64) in the cohort studies.[72] Besides SSRIs, other antidepressants which have been linked to increased risk of UGIB include mirtazapine and bupropion. A meta-analysis showed the risk of UGIB with mirtazapine to be 1.17 (95% CI: 1.01–1.38), with no significant difference in the risk between SSRIs and mirtazapine or SSRIs and bupropion.[73]

In terms of risk factors for UGIB, the most consistently reported risk factors include concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents (such as aspirin and clopidogrel), and use of both NSAIDs and antiplatelet drugs. Further, the data suggest the risk are higher during the initial phase of therapy. The concomitant use of acid-suppressive agents reduces the risk of UGIB.[71] A case series analysis that included data from 7 population-based health care databases and data of 114,835 patients with UGIB with information of 930,888 person-years of follow-up reported that the relative risk of UGIB was 2.06 (95% CI: 1.94–2.18) with SSRI monotherapy, 4.60 (95% CI: 4.09–5.17) with a combination of SSRIs and low-dose aspirin, and 6.95 (95% CI: 5.97-8.08) with a combination of SSRIs and NSAIDs.[74] Increased risk of UGIB with concomitant use of warfarin has also been reported.[75] In terms of number needed to harm (NNH), some of the authors have estimated that for one patient to develop UGIB with SSRIs, 791 patients need to be exposed to SSRIs. However, when the SSRIs are combined with NSAIDs and antiplatelet agents the NNH reduces to 160 and 294 per year, respectively.[71] In terms of duration of exposure to SSRIs, although there is a lack of consensus, some of the studies have reported the highest risk during the first 1 month of exposure to SSRIs, whereas others suggest the risk persists throughout exposure to SSRIs.[70] Other risk factors which have been reported to be associated with higher risk of UGIB with SSRIs include age more than 80 years and past history of UGIB.[76]

Hematemesis can be an acute medical emergency associated with the use of antidepressants, especially SSRIs. The assessment of a patient on SSRIs who present with hematemesis, should involve assessment for risk factors and ruling out other possible causes of UGIB which could be peptic ulcer and/or malignancy, besides other causes. The offending agent(s), should be stopped and if the patient is on concomitant medications, the same should be stopped in liaison with other specialists. Management involves stabilization of hemodynamic status and evaluating for the need for blood transfusion. Once the patient has stabilized hemodynamically, endoscopy should be considered to evaluate for other possible causes of hematemesis and addressing the same.

In patients who require further continuation of antidepressants, which are considered to be less likely to cause UGIB should be considered and concomitant use of proton pump blockers should be considered. The agents with lower risk for UGIB include tianeptin, reboxetine, SNRIs, and tricyclic antidepressants.

SEVERE INTESTINAL OBSTRUCTION

Constipation is a common side effect of many psychotropic agents. However, some of the psychotropics can lead to severe gut hypomotility, manifesting as paralytic ileus, fecal impaction, bowel obstruction, necrotizing colitis, and intestine/bowel perforations.[777879] Among the various psychotropics, antipsychotics have been most commonly reported to be associated with paralytic ileus. The antipsychotics associated with paralytic ileus include clozapine, quetiapine, olanzapine, and high potency antipsychotics.[8081] In addition, paralytic ileus is reported to be associated with the use of anticholinergic medications and tricyclic antidepressants.[80] The risk factors for paralytic ileus include older age, female gender, higher daily dose of medication (clozapine), and concomitant use of opioids.[80] Among all the antipsychotics, gut hypomotility with clozapine has received significant research attention and this has been attributed to the anti-muscarinic effects, anti-adrenergic effects, and anti-serotonergic effects of clozapine. Additional factors which contribute to the development clozapine associated gut hypomotility and paralytic ileus include cessation of smoking, delayed symptom reporting by the patients, and failure on part of the clinicians to screen patients for their bowel habits.[7882] Clozapine-induced gut hypomotility has been shown to be associated with older age, male gender, first 4 months of clozapine therapy, concomitant use of other medications which can cause constipation, higher doses, and past history of clozapine-induced gut hypomotility.[78]

The clinical presentation of paralytic ileus and other severe gut manifestations may include pain abdomen, vomiting, and constipation. On examination, the patient may be found to be in acute distress with abdominal distension, hemodynamic instability (tachycardia, hypotension, tachypnea), fever, abdominal tenderness, and reduced or absent bowel movements. In severe cases, the patient may present with clinical picture suggestive of septic shock.[7879] Whenever, paralytic ileus is suspected abdominal X-ray and/or ultrasound abdomen needs to be done, which can provide clues for the diagnosis. The management is usually supportive. Stopping of the offending agent may be sufficient in many cases to relieve the ileus. However, if a patient develops perforation peritonitis, then laparotomy may be required. Usually, rechallenge with the same agent is not done in patients with paralytic ileus. Amisulpride and aripiprazole were not been found to be associated with paralytic ileus in one of the studies.[80] In view of the high frequency of intestinal hypomotility, it is suggested that constipation in patients being considered for clozapine should be addressed before starting clozapine and other preventive measures such as monitoring of bowel habits, consumption of high fiber diet, and adequate fluid intake must be encouraged. Smoking should also be stopped prior to starting of clozapine.[78] When the patient on medications which can potentially cause gastrointestinal hypomotility, bowel habits must be monitored by clinicians during all the follow-up visits and appropriate preventive measures must be ensured.

HEPATIC INJURY

Drug-induced liver injury (DILI) has been reported with some of the psychotropic medications. The mechanisms reported for the development of DILI with psychotropics are broadly understood in three forms: Cholestasis (for example, chlorpromazine), direct hepatocellular injury (immunologically mediated or idiosyncratic metabolic damage), or a combination of both. It is suggested than 90% of the DILI is in the form of direct hepatocellular injury. Most of the DILIs are idiosyncratic, unpredictable, and not related to the dose of the medication.[83]

Further, psychotropics can also lead to indirect liver injury by increasing the risk of nonalcohol fatty liver disease (NAFLD). The medications implicated for NAFLD include antipsychotics which increase the risk or prevalence of metabolic syndrome. The most commonly implicated agents for this include olanzapine and clozapine.[83]

Direct liver injury has been reported with the use of olanzapine, clozapine, risperidone, quetiapine, and ziprasidone. This usually manifest during the initial part of the treatment. The hepatic injury caused by chlorpromazine manifest in the form of acute cholestasis. Among the antidepressants, DILI has been reported with the use of imipramine, amitriptyline, clomipramine, moclobemide, phenelzine, tianeptine, duloxetine, venlafaxine, sertraline, fluoxetine, paroxetine, citalopram/escitalopram, fluvoxamine, trazodone, nefazodone, bupropion, agomelatine, and mirtazapine.[83] According to one of the classifications imipramine, amitriptyline, nefazodone, venlafaxine, duloxetine, sertraline, bupropion, trazadone, and agomelatine are considered to have a high risk of DILI.[8485] Antidepressant-associated DILI is usually of hepatocellular pattern, with some of the molecules associated with cholestatic or mixed pattern of injury.[85]

Among the mood stabilizers, DILI has been reported to occur with carbamazepine, valproate, lamotrigine, topiramate, gabapentin and pregabalin. Very rarely, DILI has also been reported with the use of lithium. The benzodiazepines associated with DILI include diazepam, chlordiazepoxide, and flurazepam.[83]

It is also important to remember that other side effects of the same medication, for example constipation and excessive sedation can also aggravate hepatic impairment.

The clinical manifestations of DILI are usually asymptomatic or may manifest with nonspecific symptoms such as fatigue, loss of appetite, and epigastric discomfort, and pain over the liver area. Patients with cholestasis manifest with itching, yellowing of skin, and itching over the whole body. Other clinical features may include fever, rash, and arthralgia [Table 7]. It could also be indicated by increase in the serum levels of alanine aminotransferase (ALT) (3 times more than the usual), aspartate aminotransferase, alkaline phosphatase (2 times more than the usual), gamma-glutamyl transferase, and raised serum bilirubin levels (>2 mg/dL). Other investigation findings may include increase in the eosinophil count. The DILI, which is an outcome of hypersensitive reaction and is immunologically mediated is characterized by fever, rash, increased eosinophil count, and presence of auto-antibodies. It is usually seen within 1–6 weeks of starting of the implicating agent. In contrast, the idiosyncratic DILI is characterized by the absence of features of hypersensitivity reaction and it usually occurs after the longer latency period of starting of the offending agent. Chronic DILI manifests either as chronic hepatitis, liver fibrosis, and compensated or decompensated cirrhosis, autoimmune-like hepatitis, chronic cholestasis, and vanishing bile duct syndrome.

A combination of raised serum bilirubin levels, reduced serum albumin levels and increased prothrombin time (INR of ≥ 1.5), without any increase or a small increase in the aspartate aminotransferase levels, indicate severe liver injury. Ultrasound of liver may not provide much information in acute liver injury except for mild swelling [Table 8]. The patients with chronic DILI may have features of cirrhosis of liver, splenomegaly, and increase in the diameters of the portal vein.

While considering DILI, other differential diagnosis, such as overdose with other medications such as acetaminophen, use of other medications which can cause DILI, over the counter medications, use of herbal preparations, exposure to hepatotoxins, viral hepatitis, autoimmune hepatitis, malignancy (primary or secondary’s in the liver due to other malignancies), other liver diseases such as Wilson’s disease, and vascular diseases such as Budd–Chiari syndrome and liver problems associated with congenital diseases must be ruled out.[838485]

The management of DILI is guided by the severity of the injury and the clinical manifestations. Stopping of offending agent and institution of general measures [Table 4] is the first step in the management. Depending on the need, liver-protecting treatment should be initiated. As most of the DILI is mild (raised ALT, no significant increase in bilirubin levels, and no prolongation of prothrombin time) in nature, stopping of offending agent is often sufficient. However, severe DILI (raised ALT, significant increase in bilirubin levels, prolonged of prothrombin time, jaundice, and liver failure) will additionally require the use of hepatoprotective agents.

As majority of the psychotropics are metabolized through the liver, it is important to understand the safety of psychotropics in patients with liver diseases, especially among those who already have DILI. Once the patient develops DILI, while choosing psychotropics, the clinicians should remember to avoid medications that have extensive first-pass metabolism (e.g., venlafaxine, sertraline, bupropion, chlorpromazine, and quetiapine) are highly plasma protein-bound (all psychotropics with the exception of venlafaxine, lithium, topiramate, gabapentin, pregabalin, memantine) and medications that depend on the phase-I hepatic metabolic reactions (almost all psychotropics except lithium, gabapentin, topiramate, amisulpride, oxazepam, temazepam, lorazepam).[83] For the management of primary illness, antipsychotics that are less metabolized through the liver, for example, amisulpride and paliperidone should be considered. However, it is important to remember that, if conclusive evidence cannot be reached for the association of the liver injury and the ongoing antipsychotic medication than the antipsychotic medication can be continued with the monitoring of the laboratory parameters.[86]

PANCREATITIS

Pancreatitis has been reported to be a rare side effect of antidepressants, antipsychotics, and mood stabilizers. Among the various antidepressants pancreatitis has been reported with SSRIs. A meta-analysis which included data of 13898 patients with type-2 diabetes mellitus and 284131 controls from nine studies and 17548 patients with acute pancreatitis and 108,108 controls from four studies estimated the adjusted odds ratio to be 1.26 (95% CI: 1.13–1.40), with higher risk during the initial 2 weeks of therapy.[87] Among the other psychotropic agents, pancreatitis has been reported with the use of clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and valproate/valproic acid.[988]

Badalov et al. (2007)[89] gave a classification of drug-induced pancreatitis and categorized the drug-induced pancreatitis into 4 classes. Class-I drugs include those medications for which there is at least 1 case report in which recurrence has been documented on rechallenge. Class-II includes medications for which consistent latency (defined as the time from initiation of medication to the development of disease) in 75% or more of the reported cases have been documented. Class-III includes medications for which 2 or case reports have been documented, but there is no information about rechallenge and a consistent latency period. Class-IV includes medications for which only 1 case report has been published. Most of the psychotropics are categorized in Class-III.[9]

The risk factors for antipsychotic-associated pancreatitis include use of alcohol, presence of diabetes mellitus, history of cholelithiasis, and polypharmacy with concomitant use of other drugs which are linked to the development of pancreatitis.[88] Majority of the patients with acute pancreatitis present with acute abdomen. The assessment of a patient suspected to have acute pancreatitis should include confirmation of diagnosis (by ruling out other possible causes of the acute abdomen), ascertainment of cause of pancreatitis, and ruling out other causes of pancreatitis. The history should focus on obtaining the information about other medication intake, comorbid physical illnesses (triglyceridemia, diabetes mellitus, and hypocalcemia), and comorbid substance use. The investigation panel must include ascertainment of serum amylase and lipase levels and ultrasound of abdomen. Other investigations are guided by the differential diagnosis and severity of the pancreatitis [Table 8]. The management involves stoppage of the offending agent(s), achieving the hemodynamic stability, use of antibiotics, and preventing secondary complications. Rarely, patients with severe pancreatitis may require surgical intervention [Table 9].

Once patient is clinically stabilized, alternative psychotropics must be considered to manage the underlying psychiatric disorder. There is a lack of sufficient evidence for rechallenge with the same agent in patients who develop pancreatitis with a particular psychotropic agent. Hence, a rechallenge should not be considered, if other options are available.

PRIAPISM

Priapism is a rare side effect of psychotropics, which can present as a medical-surgical emergency. It is associated with the use of antipsychotics and antidepressants like trazadone. In fact, some of the existing literature implicates antipsychotic medications as one of the common causes of drug-induced priapism.[10] The commonly implicated antipsychotics include phenothiazines (chlorpromazine, thioridazine, fluphenazine, perphenazine, mesoridazine, and thiothixene), haloperidol, zuclopenthixol, molindone, risperidone, ziprasidone, olanzapine, quetiapine, aripiprazole, and clozapine.[1090] The antidepressants commonly associated with priapism include trazodone, nefazodone, bupropion, citalopram, fluoxetine, sertraline, paroxetine, and venlafaxine.[90] Other psychotropics which have been shown to be associated with priapism include buspirone, hydroxyzine. It can occur anytime during use of antipsychotic agent, i.e., during the initial course of treatment, during the long-term use of antipsychotics or after the change in the dose of the antipsychotic medication.[90] Priapism is usually attributed to the alpha-adrenergic blocking properties of the psychotropic, with agents having higher potential, associated with higher risk of developing priapism.[10] It is reported both in men and women (in the form of clitoral priapism).[10] Clitoral priapism has been reported with the use of trazadone, nefazodone, citalopram, bupropion and olanzapine. Antipsychotic-induced priapism is usually understood as an ischemic priapism. Some of the risk factors associated with psychotropic associated priapism reported in the literature include a history of prolonged and painful erections, diabetes mellitus, polypharmacy (either another antipsychotic) especially with agents having high alpha-adrenergic blocking properties, antidepressant (with alpha-adrenergic blocking properties or those which inhibit the metabolism of the antipsychotics at the CYP450 enzyme level), lithium (especially when used with lithium), antiretroviral therapy (by inhibiting the metabolism of antipsychotics), concomitant use of medications like terazosin (which is alpha-1-selective adrenergic antagonist), tamsulosin, prazosin, alfuzosin, hydralazine, sildenafil, tadalafil, and vancomycin. While evaluating the patients besides the medications, other causes of priapism such as malignancies, trauma to the perineum, use of medications such as testosterone, gonadotropin-releasing hormone, heparin, warfarin, alprostadil, papaverine, propofol, methylphenidate, atomoxetine, scorpion sting, black widow spider sting should also be kept in mind.[1190] In addition, metabolic disorders such as amyloidosis, gout, and substance use such as alcohol, cannabis, and cocaine should also be enquired.[1190]

While establishing the diagnosis, the clinician should make effort to distinguish the high flow and low-flow priapism. The antipsychotic-induced priapism is usually low-flow ischemic type of priapism. The high-flow priapism is nonpainful and characterized by retention of well-oxygenated blood in the corpora cavernosa, whereas the low-flow priapism is painful and is characterized by accumulation of deoxygenated blood, is prolonged, and can lead to irreversible damage.

Patients with priapism usually present with prolonged erection, which may or may not be painful. While history taking the clinicians should focus on collecting information about the duration of erection, level of pain, and past history of prolonged painful erections. In addition, information with respect to all the ongoing medications, use of any erectogenic medications in the recent past, use of opioids or other drugs of abuse, and hematological abnormalities such as sickle cell anemia or other hemoglobinopathies and hypercoagulable states, and history of trauma to the local site must be enquired [Table 7]. The local examination should focus on proper examination of genitalia, perineum, and abdomen. While examining the penis, the clinician should try to distinguish the ischemic low flow priapism from the high-flow priapism (in ischemic priapism, the glans will be soft, but the corpora is fully rigid and tender) [Table 7]. The specific investigations in patients with priapism will include the assessment of coagulation profile and carrying out corporal blood gas analysis that can aid in distinguishing arterial and ischemic priapism [Table 8].

The management involves removing the offending agent(s) and penile aspiration. If this does not help then the use of phenylephrine or surgical intervention (penile shunt surgery) may be considered [Table 9].

URINARY RETENTION

Occasional patients on psychotropics can present with acute urinary retention. Some of the patients may also present with chronic urinary retention. The urinary retention is linked to the anticholinergic and adrenergic side effects of psychotropic medications. The available data in the form of meta-analysis suggest that the incidence of urinary retention with antidepressants (especially TCAs and SNRIs > SSRIs) is higher than the placebo.[91] Similarly, urinary retention has also been reported with antipsychotics, such as phenothiazines (chlorpromazine, thioridazine) and thioxanthenes (chlorprothixene), olanzapine clozapine, diazepam, baclofen, amphetamines, carbamazepine, and opioid analgesics.[12919293]

Available data suggest that elderly are at higher risk of medication-related urinary retention and this is attributed to the presence of benign prostatic hyperplasia. Additional risk factors include concomitant use of other medications, such as anticholinergic agents, opioids, alpha-adrenoreceptor agonists, benzodiazepines, NSAIDs, calcium channel blockers, and detrusor relaxants that could also contribute to urinary retention.[94]

The assessment of a patient presenting with urinary retention require review of all the medications, looking for other anticholinergic side effects, and considering other causes of urinary retention (such as bladder stone, urethral stricture, meatal stenosis, paraphimosis, phimosis, penile constricting bands, prostate cancer, or any other external mass blocking the urinary passage). In addition, infective (such as prostatitis, balanitis, and prostatic abscess), traumatic (penile trauma, abscess, and laceration), and neurological (e.g., Guillain–Barre Syndrome, spinal cord lesions, herpes zoster, diabetic neuropathy, etc.) causes of urinary retention must also be ruled out.[12] In females, who present with acute urinary retention, causes like organ prolapse (cystocele, rectocele, uterine prolapse), pelvic mass (gynecologic malignancy, uterine fibroid, ovarian cyst), retroverted impacted gravid uterus, acute vulvovaginitis, vaginal lichen planus, vaginal lichen sclerosis, vaginal pemphigus and dysfunction of the urethral sphincter should be kept in mind.[12]

The investigation panel [Table 8] is determined by the possible differential diagnosis. The drug-induced urinary retention can be managed by reducing the dose or stopping the offending agent(s) [Table 9].[12]

CONCLUSION

The present guidelines provide details of the management of the patients who encounter medical emergencies due to psychotropic medications. These guidelines cover some of the specific manifestations such as seizures, glaucoma, agranulocytosis, diabetic ketoacidosis, myocarditis, and aspiration pneumonia. It must be acknowledged that each patient’s health conditions, medications profile, and impact of medications might be different, and cognizance should be taken of the seriousness of the medical emergency, the potential causal relationship with the psychotropic medications, and the final necessity of the medication.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.