Hospitalists are often asked to consult on inpatient psychiatric patients and co-manage pre-existing medical conditions. In addition, approximately 30-60% of inpatients have psychiatric comorbidities. Given that the majority of these patients are receiving psychiatric medications, it is important for hospitalists to be well versed in the complications of psychiatric medications. Complications of psychiatric medications range from mild to life threatening and include:
Common side effects
Serious adverse drug responses
II. Identify the Goal Behavior
An adverse drug reaction is defined as a response to drug that is unintended and occurs at the dose normally used for prophylaxis, diagnosis, or therapy. Therefore, an adverse drug reaction is an adverse event with a causal link to a drug. Determining if a medication is causing a specific adverse event and which specific medication is to blame can be difficult. In order to do this, hospitalists must understand the nature, severity, causality, and management of adverse drug reactions associated with pharmacologic psychiatric treatment.
Common side effects: gastrointestinal (GI) disturbance, somnolence, insomnia, weight gain, and sexual dysfunction
Serious adverse drug responses: syndrome of inappropriate antidiuretic hormone syndrome (SIADH), serotonin syndrome (characterized by agitation, tachycardia, fever, myoclonus, and ataxia)
Serotonin syndrome: concomitant use of monoamine oxidase (MAO) inhibitors or other serotonergic drugs (linezolid, tramadol, anti-migraine and anti-seizure medications, herbal supplements, illicit drugs, and many others)
Withdrawal syndrome: abrupt withdrawal can result in irritability, disequilibrium, flu-like symptoms, gastrointestinal symptoms, paresthesias and sleep disturbances
(venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran)
Side effect profile is very similar to SSRIs with the following exceptions
Lower incidence of sexual dysfunction
May result in hypertension
Levomilnacipran has more norepinephrine effect so may increase heart rate and blood pressure
Common side effects: headache, dry mouth, GI disturbances, orthostatic hypotension, weight gain, sexual dysfunction
Serious adverse drug responses: elevated liver transaminases, pyridoxine deficiency resulting in paresthesias and weakness
Hyperadrenergic crisis: concomitant use of adrenergic agonists or consumption of tyramine-containing foods
(characterized by occipital headache, nausea, vomiting, diaphoresis, tachycardia, and severe hypertension)
MAO inhibitor overdose is quite dangerous, with rates of death higher than other antidepressants
May result in serotonin syndrome, neuromuscular excitability, seizures, arrhythmias, and cardiovascular collapse
(amitriptyline, nortriptyline, clomipramine, etc.)
Common side effects: sedation, GI disturbances, sexual dysfunction, orthostatic hypotension, anticholinergic effects, and sexual dysfunction
Serious adverse drug responses: arrhythmia (class I antiarrhythmic): can lead to prolongation of the PR, QRS, and QT intervals resulting in heart block or ventricular arrhythmias, increased risk of myocardial infarction
Serotonin syndrome if used with MAO inhibitors
Overdose syndrome: exaggeration of common side effects with sedation, anticholinergic delirium, hypotension as well as life threatening ventricular arrhythmias
Vilazodone is a serotonin reuptake inhibitor and 5-HT1A receptor partial agonist.
Common side effects: GI side effects (diarrhea, nausea, vomiting); headache
Drug-drug interactions:serotonin syndrome
Vortioxetine is a serotonin reuptake inhibitor, 5-HT1A receptor agonist, 5-HT1B partial agonist, also antagonist of 5-HT3, 5-HT1D, 5-HT7
Common side effects: nausea, vomiting, insomnia
Drug-drug interactions: serotonin syndrome
Bupropion is a dopamine and norepinephrine reuptake inhibitor
Common side effects: dry mouth, constipation, insomnia, weight loss
Serious adverse drug responses: seizures (usually doses >300–450 mg/day, more common with immediate release formulation than extended release)
Common side effects: daytime fatigue, dizziness, nausea, weakness, and ataxia
Serious adverse drug responses: anterograde amnesia, increased risk of motor vehicle accidents and accidental injuries, increased risk of falls in the elderly, and respiratory depression
Concomitant use with antihistamines and alcohol may intensify sedation, ataxia, and respiratory depression
Overdose syndrome: can result in sedation, delirium, ataxia, respiratory depression, hypotension, and coma. Can be fatal.
Withdrawal syndrome is similar to alcohol withdrawal:
Mild withdrawal: anxiety, tremor, diaphoresis, tachycardia, and hypertension
Delirium tremens: autonomic instability, delirium, psychosis
Common side effects: sedation, tremor, GI disturbance, hypothyroidism, weight gain
Serious adverse drug responses: renal failure, nephrogenic diabetes insipidus, polydipsia, hypocalcaemia, sinoatrial node slowing, atrioventricular blockade
Overdose syndrome: severe sedation, delirium, myoclonus, seizure, and arrhythmia
Common side effects: sedation, tremor, GI disturbance, alopecia, weight gain
Serious adverse drug responses: pancreatitis, elevated liver transaminases, thrombocytopenia, leucopenia
Overdose syndrome: central nervous system (CNS) depression
Withdrawal syndrome: risk of seizure
Common side effects: sedation, tremor, ataxia, diplopia, GI disturbance, mild benign rash
Serious adverse drug responses: Stevens-Johnson syndrome, SIADH, elevated liver transaminases. aplastic anemia, slowed cardiac conduction
Overdose: increased severity of neurologic side effects, high grade atrioventricular block, coma
Withdrawal: risk of seizure
Common side effects: headache, nausea, rash including erythema multiforme
Serious adverse drug responses: hypersensitivity syndrome (including DRESS – see chapter for full details), Stevens-Johnson syndrome, toxic epidermal necrolysis
(haloperidol, chlorpromazine, fluphenazine, etc.)
Common side effects: weight gain, photosensitivity, sexual dysfunction, hyperprolactinemia, orthostasis
Serious adverse drug responses: acute dystonia, tardive dyskinesia, extrapyramidal symptoms (antipsychotic-induced parkinsonism), neuroleptic malignant syndrome (NMS), QT prolongation
Overdose syndrome: lethargy, delirium, cardiac arrhythmias, hypotension, pronounced extrapyramidal symptoms (EPS), seizure, and death
Side effects vary among each drug in this class:
All have a lower risk of tardive dyskinesia and extrapyramidal side effects compared to typical antipsychotics
Most result in significant weight gain and metabolic side effects (glucose intolerance and hyperlipidemia)
Black box warning: increased risk of cardiovascular events and death with the use of atypical antipsychotics in patients with dementia
Common side effects: dizziness, orthostasis, headache, weight gain, glucose intolerance
Serious adverse drug responses: EPS, hyperprolactinemia, neuroleptic malignant syndrome
Overdose syndrome: hypotension, sedation
Common side effects: dizziness, sedation, headache, GI disturbance, very minimal weight gain and glucose intolerance
Serious adverse drug responses: EPS (rare), QT prolongation is common but only one case of torsades in the literature
Overdose syndrome: sedation and dysarthria; no cardiotoxicity
Common side effects: headache, anxiety, akathisia, GI disturbance
Serious adverse drug responses: EPS (other than akathisia) is rare; hyperprolactinemia, glucose intolerance, weight gain, neuroleptic malignant syndrome are also not common
Overdose syndrome: sedation, vomiting, tremor, orthostatic hypotension; no cardiotoxicity
Common side effects: sedation, dry mouth, constipation, dizziness, orthostasis, tremor, increased appetite, frequent weight gain, hyperlipidemia
Serious adverse drug responses: EPS, hyperprolactinemia and NMS are rare, six-fold increase in development of diabetes, diabetic ketoacidosis (DKA) has been reported in the first month of treatment, elevation of liver transaminases with risk of progression to liver failure
Overdose syndrome: lethargy; no cardiotoxicity
Common side effects: anticholinergic side effects, sedation, orthostatic hypotension, sialorrhea; during the first initial weeks of treatment, drug induced fever and tachycardia are common
Severe adverse drug responses: metabolic side effects similar to olanzapine, agranulocytosis, seizure, myocarditis, cardiomyopathy, elevated liver transaminases, and neuroleptic malignant syndrome
Overdose syndrome: delirium, lethargy, tachycardia, hypotension, and respiratory failure; cardiac arrhythmias and seizures may occur, and overdose can be fatal
Newer atypical antipsychotics include a senapine, lurasidone, iloperidone, cariprazine, and brexpiprazole
III. Describe a Step-by-Step approach/method to this problem.
Step 1: Understand the definition of adverse drug reactions
Step 2: Understand and document the nature of the side effects
Onset of signs and symptoms
Description of signs and symptoms
History of similar reactions
Complete review of current medication list and changes
Step 3: Identify and document the severity of drug reaction
Critical lab values, vital signs, or physical exam findings
Identification of severe drug toxicity syndromes
Step 4: Identify the strength of the causal relationship between the drug and the adverse event
This requires considering the temporal relationship between drug initiation or dosage adjustment and onset of symptoms, as well as the consistency between signs and symptoms and known side effects of a given medication. Use the following set of criteria to assess the grades of certainty that an event is linked to a drug.
Occurs in a plausible time relationship to drug administration
Cannot be explained by concurrent disease or other drugs or chemicals
Appropriate resolution of the clinical event with withdrawal of the drug
Return of symptoms with rechallenge of the drug
Occurs within a reasonable time sequence to administration of the drug
Unlikely to be attributed to concurrent disease or other drugs or chemicals
Follows a clinically reasonable response on withdrawal (dechallenge)
Rechallenge information is not required to fulfill this definition
Occurs within a reasonable time sequence to administration of the drug
Can also be explained by concurrent disease or other drugs or chemicals
Information on drug withdrawal may be lacking or unclear
Temporal relationship to drug administration makes a causal relationship improbable
Underlying disease process, drugs or chemicals provide a more plausible explanation of the clinical event
Step 5: Manage the adverse response
Discontinue the offending medication
Treat the side effects
Follow the clinical side effects, such as resolution of agranulocytosis after discontinuation of clozapine
Step 6: Document the seriousness and causation of a drug and describe the event on the patient’s chart
Step 7: Report serious and unexpected drug events
IV. Common Pitfalls.
Psychiatric medications are commonly used in hospitalized patients. While they play an important role in medical care, it is imperative to consider their potential complications. Due to the complexity of hospitalized patients, recognizing characteristic clinical manifestations can be difficult. In these cases, discontinuation of an offending medication, treating intoxication, or managing withdrawal syndromes can be life-saving. On the other hand, mild side effects can often be managed supportively or by lowering and/or dividing the dose rather than stopping the medication all together. Finally, the entire medication regimen must be analyzed in conjunction as some adverse responses result from drug-drug interactions rather than the effects of a single drug in isolation.
V. National Standards, Core Indicators and Quality Measures.
The US Food and Drug Administration (FDA) has set up a voluntary reporting system for physicians called MedWatch that encourages and facilitates the reporting of serious, unexpected adverse drug reactions. MedWatch forms can be obtained from the FDA website (www.fda.gov/medwatch/report/hcp.htm). The FDA defines a serious reaction as one resulting in death, a life-threatening experience, prolonged or initial hospitalization, significant or persistent disability, or a congenital anomaly.
The Joint Commission requires hospitals to have written procedures for adverse drug reactions (ADR) reporting, evaluating, and monitoring. In addition, it requires institutions to have a means in which ADRs can be utilized to improve patient care.
VI. What's the evidence?
Nebeker, J, Branch, P, Samore, M. “Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting”. Ann Intern Med. vol. 140. 2004. pp. 795-801.
Riedl, M, Casillas, A. “Adverse drug reactions: types and treatment options”. Am Fam Physician. vol. 68. 2003. pp. 1791-1790.
Huffman, J, Stern, T, Stern, T, Rosenbaum, J, Fava, M, Biederman, J, Rauch, S. “Side effects of psychotropic medications”. Massachusetts General Hospital Comprehensive Clinical Psychiatry. 2008. pp. 705-720.
Smith, F, Wittmann, C, Stern, T. “Medical complications of psychiatric treatment”. Crit Care Clin. vol. 24. 2008. pp. 635-656.
Boggs, T, DiPaula, B, Siddiqi, S. “Adverse drug reactions in hospitalized psychiatric patients”. Ann Pharmacother. vol. 44. 2010. pp. 819-825.
Sahli, ZT, Banerjee, P, Tarazi, FI. “The Preclinical and Clinical Effects of Vilazodone for the Treatment of Major Depressive Disorder”. Expert Opin Drug Discov. vol. 11. 2016 May. pp. 515-23.
Heitmiller, DR. “Serotonin syndrome: a concise review of a toxic state”. R I Med J (2013). vol. 97. 2014 Jun 2. pp. 33-5.
Baldwin, DS, Chrones, L, Florea, I. “The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies”. J Psychopharmacol. vol. 30. 2016 Mar. pp. 242-52.
Murru, A, Popovic, D, Pacchiarotti, I, Hidalgo, D, León-Caballero, J, Vieta, E. “Management of adverse effects of mood stabilizers”. Curr Psychiatry Rep. vol. 17. 2015 Aug. pp. 603
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- I. Problem/Challenge.
- II. Identify the Goal Behavior
- III. Describe a Step-by-Step approach/method to this problem.
- IV. Common Pitfalls.
- V. National Standards, Core Indicators and Quality Measures.