Hospital Medicine

Complications of psychiatric medications

I. Problem/Challenge.

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

  • Drug-drug interactions

  • Intoxication syndromes

  • Withdrawal syndromes

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.

Antidepressant Medications

Selective Serotonin Reuptake Inhibitors (SSRI) (citalopram, fluoxetine, paroxetine, sertraline, fluvoxamine)

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)

Drug-drug interactions:

  • 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

Serotonin-Norepinephrine Reuptake Inhibitors (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

Monoamine Oxidase Inhibitors (isocarboxazid, phenelzine)

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

Drug-drug interactions:

  • Hyperadrenergic crisis: concomitant use of adrenergic agonists or consumption of tyramine-containing foods

    (characterized by occipital headache, nausea, vomiting, diaphoresis, tachycardia, and severe hypertension)

  • Serotonin syndrome

Overdose syndrome:

  • 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

Tricyclic Antidepressants (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

Drug-drug interactions:

  • 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

Novel Antidepressants

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)

Benzodiazepines

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

Drug-drug interactions:

  • 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

  • Seizures

  • Delirium tremens: autonomic instability, delirium, psychosis

Mood Stabilizers

Lithium

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

Valproic acid

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

Carbamazepine

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

Lamotrigine

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

Typical Antipsychotics (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

Atypical Antipsychotics

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

Risperidone

Common side effects: dizziness, orthostasis, headache, weight gain, glucose intolerance

Serious adverse drug responses: EPS, hyperprolactinemia, neuroleptic malignant syndrome

Overdose syndrome: hypotension, sedation

Ziprasidone

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

Aripiprazole

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

Olanzapine

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

Clozapine

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.

Certain

  • 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

Probable/likely

  • 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

Possible

  • 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

Unlikely

  • 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. Mosby Elsevier. 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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