Updates in Pharmacology: Interactions and Adverse Effects of Psychiatric Medications

Authors: Erica Bates, MD; Philip Magidson, MD MPH; Robert Brown, MD; Megan Donohue, MD; Akilesh Honosage, MD
Editors: Michael C Bond, MD FAAEM; Kelly Maurelus, MD FAAEM
Originally Published: Common Sense March/April 2017

Over the past decade, the number of psychiatric medications dispensed has increased dramatically and now annually numbers in the tens of millions. As Emergency Physicians now frequently encounter patients on psychiatric medications, understanding potential complications and potentially life threatening reactions is necessary. This journal review covers common potential side effects, adverse reactions, and drug-drug interactions of various psychiatric medications commonly found in the ED.

Gill SS, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med. 2009 May 11;169(9): 867-73.

Worldwide, over 24 million patients have dementia and many are prescribed cholinesterase inhibitors. While the true efficacy of these medications is still being determined, the side effect profiles are well known and frequently not discussed. Syncope is a one common side effect resulting in increased morbidity and healthcare utilization. The authors of this study sought to identify the relationship between the use of cholinesterase inhibitors and syncope-related outcomes.

This large, population-based cohort study was conducted in Canada. The investigators used a healthcare database system to identify 19,803 community dwelling adults over the age of 65 with a diagnosis of dementia who had been prescribed a cholinesterase inhibitor. Specifically, these medications were donepezil, galantamine and rivastigmine. The same database was also used to establish a control group of 61,499 patients with dementia and similar demographics who had not taken the aforementioned medications within the year preceding study enrollment. These two groups were then analyzed for four main outcomes: hospital visits for syncope, hospital visits for bradycardia or complex atrioventricular block, premature pacemaker insertion, and hip fracture.

The results showed that patients receiving cholinesterase inhibitors were more likely than controls to experience each complication, specifically, for a hospital visit for syncope (31.5 vs 18.6 events per 1000 person years; adjusted hazard ratio, 1.76; 95% CI, 1.57-1.98); for a hospital visit for bradycardia (6.9 vs 4.4 events per 1000 person-years; hazard ratio 1.69; 95% CI 1.32-2.15); for permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; hazard ratio 149;95% CI 1.12-2.00), and for hip fracture (22.4 vs 19.8 events per 1000 person-years; hazard ratio 1.18; 95% CI 1.04-1.34).

Cholinesterase inhibitors increase vagal tone, which can lead to syncope. Although the study findings are observational, they are consistent with the pharmacologic mechanism and resulting physiologic response one could expect in patients taking these medications. While EPs typically do not prescribe these medications, we should be aware of their side effect profile. As many dementia patients are poor historians, the EP may have to perform a record review or contact family in order to determine the patient’s medication list. Identifying a potential cause for syncope or bradycardia in the ED may allow patients to forego potentially invasive procedures, such as pacemaker insertion, when something as simple as a medication reconciliation might accomplish a similar goal.

Dols A, et al. The prevalence and management of side effects of lithium and anticonvulsants as mood stabilizers in bipolar disorder from a clinical perspective: a review. Int Clin Psychopharmacol. 2013 Nov;28(6): 287-96.

Medication side effects are distressing to patients and are often a cause of poor compliance. This is particularly true of mood stabilizing agents, including lithium, valproate, lamotrigine, and carbamazepine. This paper reviewed side effects of these medications, all commonly used for the treatment of acute mania or bipolar depression. The authors reviewed all PubMed publications that reported data on side effects in patients with bipolar disorder through December 2012. Side effects were reviewed systematically including neurologic, gastrointestinal, metabolic, endocrinologic, nephrogenic, dermatologic, cognitive, sexual, hepatologic, hematologic, and teratogenic. Of note, this study did not review efficacy of medications on treatment of the underlying mood disorder.

Tremor is the most common neurologic side effect and is present in up to 65% of patients using lithium and 1-6% of those on valproate. Prevalence is decreased by avoidance of caffeine, nicotine, and SSRIs or with the concomitant use of propranolol or vitamin B6.

Gastrointestinal side effects including nausea, vomiting, and diarrhea occur in up to 50% of patients taking lithium or valproate.

Hypothyroidism is the most common endocrine side effect and occurs in 5% of patients taking lithium, which inhibits thyroid hormone secretion by several mechanisms. This usually develops within the first few years of treatment, and up to 2% of lithium-treated patients require treatment with levothyroxine. Additional risk factors for the development of hypothyroidism include iodine deficiency, cigarette smoking, and the presence of autoantibodies. Valproate and carbamazepine may less commonly result in hypothyroidism.

By inhibiting ADH, lithium may cause nephrogenic diabetes resulting in polyuria, dehydration, thirst, and polydipsia. Use of lithium for ten or more years is also associated developing chronic renal failure. Therefore, monitoring of renal function and lithium levels is imperative.

Cognitive side effects including loss of memory and motor speed have been most studied with lithium. The previously discussed side effect of hypothyroidism may also result in cognitive decline. After excluding other potential causes of cognitive decline, therapeutic strategies such as focusing attention, rehearsing information, use of mnemonics, and use of visual concepts may help patients manage cognitive side effect.

Sexual side effects, primarily decreased sexual desire, have been reported in up to 14% of patients taking lithium. Carbamazepine may have this effect by increasing sex hormone-binding globulin, which can diminish the activity of sex hormones. Few options exist to counteract this side effect, but alternative medications for bipolar such as oxcarbazepine or lamotrigine have not been associated with changes in hormone levels.

Hepatologic side effects usually manifest as asymptomatic transaminitis or hyperammonemia and are both dose related. These occur in up to 40% of patients taking valproate, though severe hepatotoxicity is very rare. Valproate induced hepatic encephalopathy marked by tremor, ataxia, drowsiness and disorientation is also rare and carnitine is being explored as a treatment.

Transient leucopenia is most notable hematologic effect of mood stabilizers, occurring in approximately 10% of patients taking carbamazepine. White blood cell counts may decline by 25% but usually return to baseline without discontinuation of therapy. Carbamazepine should only be discontinued if the WBC falls below 3000, neutrophils fall below 1000, or infection is present.

Many mood-stabilizing agents are teratogenic, particularly during the first trimester. Lithium increases the risk of cardiac abnormalities, such as Ebstein’s anomaly, 10-20 fold. Valproate use during the first trimester is associated with a 5-9% risk of neural tube defects, as well as atrial septal defects, cleft palate, hypospadias, polydactyly, and craniosynostosis. Carbamazepine is associated with a 1% risk of spina bifida, total anomalous pulmonary venous return, cleft lip, diaphragmatic hernia, and hypospadias. Lamotrigine use is the only mood stabilizer reviewed here that did not increase risk of major birth defects. Patients taking mood stabilizers who are found to be pregnant may require medication adjustment or substitution. However, medications should not be stopped abruptly; rather the patient should be strongly encouraged to discuss their medications and pregnancy with their psychiatrist.

Fortunately, most side effects of mood stabilizers are temporary and diminish over time. Prevalence is decreased by use of extended release formulations, temporary dose reduction, and slow titration. Risk of side effects increase with patient age and medication dose. Therefore, it is worth remembering that when used in combination valproate can increase lamotrigine levels and carbamazepine can lower lamotrigine levels. This review serves as a reminder that mood stabilizers may be the cause of various symptoms which patients seek ED evaluation. Awareness of the side effect profile of these medications can help EPs formulate a more complete differential diagnose and treatment plan for these patients.

Warnock JK, Morris DW. Adverse cutaneous reactions to mood stabilizers. Am J Clin Dermatol. 2003 Jan 4(1): 21-30.

Mood stabilizing medications, such as carbamazepine, valproate, topiramate, gabapentin, and oxcarbazepine, are associated with a higher risk of severe cutaneous reactions than many other psychotropic medications. This article reviewed dermatologic complications of mood stabilizers, which can range from benign skin eruptions to life-threatening reactions.

Exanthematous rash, an erythemic maculopapular eruption often resembling measles, is a relatively common (>1%) side effect of mood stabilizers. This rash may spread across the entire body, including the mucosa, palms, and soles. Carbamazepine, valproate, topiramate, and gabapentin are also associated with photosensitivity reactions in sun-exposed areas, typically occurring within several days of starting the medication. The phototoxic form causes erythema, edema, hyperpigmentation, and possible desquamation in exposed areas. Photoallergic reactions occur 1-2 weeks after medication initiation and produce an immunologically mediated response which can include papular, vesicular, eczematous, lichenoid, bullous, or urticaria lesions. Carbamazepine, lithium, valproate, gabapentin, and oxcarbazepine are associated with drug induced alopecia and psoriatic eruptions. Drug discontinuation generally improves both conditions, although patients with more extensive or severe symptoms may need additional treatment by a dermatologist.

Carbamazepine, lamotrigine, oxcarbazepine, and valproate are associated with systemic hypersensitivity reactions. These events generally occur within two months of starting the medication and are characterized by fever, rash, and organ dysfunction, such as hepatitis or renal impairment. Patients may initially present with fever, malaise, and pharyngitis before onset of the rash, making the diagnosis more challenging. Treatment includes discontinuing the trigger medication, systemic steroids, and antihistamines.

Erythema multiforme is a cutaneous condition characterized by red macules, papules, vesicles, and most classically by target lesions, which can be distributed symmetrically over the body. It generally occurs within days of medication use and is associated with carbamazepine, valproate, lamotrigine, gabapentin, and oxcarbazepine. The lesions may progress to mucosal involvement and subepidermal separation of up to 10% of body surface area (BSA). If suspected, the medication in question must be immediately discontinued. Dermatology should be consulted and the patient should be monitored closely for progression.

Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are life-threatening conditions marked by subepidermal desquamation of the skin and mucosal surfaces. Skin loss involving 10-30% BSA is considered SJS, and >30% BSA sloughing is classified as TEN. These patients face similar risks as severe burn patients such as fluid loss, electrolyte disturbance, and severe infection. SJS carries a 10% mortality rate, which increases to 45% with TEN. Care includes immediately stopping the responsible medication, pain control, fluid and electrolyte replacement, infection management, and typically transfer to a burn center. Of note, concomitant use of lamotrigine and valproate or carbamazepine increases the risk of SJS and TEN.

As mood stabilizing drugs are associated with multiple cutaneous disorders, some deadly, a high index of suspicion and thorough medication history is necessary for all patients who potentially takes these medications.

Rasimas JJ, Liebelt EL. Adverse effects and toxicity of the atypical antipsychotics: what is important for the pediatric emergency medicine practitioner. Clin Pediatr Emerg Med 2012 Dec 1; 13(4): 300-310.

Use of Atypical antipsychotic (AAP) medications, such as risperidone, aripiprazole, and olanzapine, in children of all ages has significantly increased over the past two decades. In 1996, 6.8% of all antipsychotics prescribed in children were AAPs while in 2001 95.9% are AAPs. This increase in prescriptions can be explained by the growing list of conditions that show benefit with atypical antipsychotics, including acute agitation, psychosis, bipolar disorder, ADHD, oppositional defiant disorder, conduct disorder, and autism. However, with this large increase in use comes a significant increase in ED visits for side effects and overdoses.

First generation, or typical, antipsychotics are classified as either high or low potency based on their affinity for the Dopamine 2 (D2) receptor. Higher potency D2 receptor antagonism, as seen with haloperidol, results in a higher rate and severity of extra pyramidal symptoms (EPS). Lower potency antipsychotics, such as chlorpromazine, have a larger anticholinergic effect and thus are able to counteract the risk of EPS, but have a resultant increase in antimuscarinic effects. AAPs have even lower potency for the D2 receptor, and add 5-hydroxytryptamine (5-HT) receptor antagonism. This lowers the incidence of EPS but increased the overall number of potential side effects.

Acute dystonic reactions such as oculogyric crisis, torticollis, or laryngeal dystonia can develop within hours to weeks of initiating or changing dosages and can often be mistaken for a seizure. Neuroleptic malignant syndrome (NMS) can occur with all antipsychotics. NMS often presents within 2-4 weeks of beginning treatment or changing dosage, but can also occur with dehydration or febrile illness. Other side effects such as akathisia, Parkinsonism, and tardive dyskinesia can often be mistaken for other psychiatric or neurological disorders.

Most AAPs are associated with significant weight gain, insulin resistance, and dyslipidemia. These effects are most common with clozapine, olanzapine, risperidone, quetiapine, and aripiprazole. These effects can be socially debilitating, especially for children.

AAPs are also associated with QT prolongation and complications from this such as torsades de pointes. Without an underlying genetic QT prolongation, the changes caused by AAPs are often not lethal; however, they may be in patients with underlying cardiac disease. Screening electrocardiograms are controversial, especially in children without underlying cardiac disease, but a thorough family history of sudden death or prolonged QT should be taken before starting any patient on antipsychotics.

AAPs have a higher incidence of anticholinergic and antimuscarinic symptoms. Such as dry mouth, urinary retention, orthostatic hypotension, and dizziness. All antipsychotics, including AAPs, may also lower the seizure threshold.

Due to their widespread use, toxic ingestion of AAPs has increased rapidly in recent years. Although respiratory depression is uncommon, central nervous system (CNS) symptoms may include drowsiness, somnolence, or coma. The anticholinergic side effects can manifest as agitation, delirium, or hallucinations. Cardiovascular symptoms may include tachycardia, hypotension, and QT prolongation. However, there have been no known cases of torsades in children due to acute overdose. Management is largely supportive, but activated charcoal can be used if ingested within 1-2 hours. Whole bowel irrigation may be useful in ingestions of sustained release formulations. In rare circumstances, lipid emulsion may even be considered. Treatment should be based on cardiopulmonary monitoring and correction of electrolyte abnormalities.

Ramsey TD, Lau TT, Ensom MH. Serotonergic and adrenergic drug interactions associated with linezolid: a critical review and practical management approach. Ann Pharmacother. 2013 Apr; 47(4): 543-60.

This literature review was drawn from English language articles in PubMed, MEDLINE, EMBASE, and International Pharmaceutical Abstracts to describe human studies of serotonergic and adrenergic drug interactions with linezolid. The authors analyzed 3 prospective, randomized controlled trials, 6 retrospective studies, and 31 case reports for signs of serotonin toxicity as defined by the Hunter Serotonin Toxicity Criteria or Sternbach’s Criteria. They used the Horn Drug Interaction Probability Scale to assess the probability of drug interactions in case reports. The number of healthy volunteers in the 3 prospective studies was small (14 each for interactions of linezolid with dextromethorphan, propanolamine, and pseudoephedrine). There were 32 cases identified from the retrospective studies and case reports, the former pooled from phase 3 and 4 randomized controlled trials and chart reviews with more than 5,000 patients.

The authors conclude there are no clinically relevant interactions between linezolid and dextromethorphan, phenylpropanolamine, or pseudoephedrine, though the latter two do raise average blood pressure 14 and 32 mmHg respectively. The incidence of serotonin syndrome in the largest retrospective analysis was 0.24% and not significantly different from a comparator control. The incidence from chart reviews calculated from much smaller populations of from 24-72 patients showed incidence rates as high as 4% for medications such as sertraline, venlafaxine, mirtazapine, and buspirone. Case reports existed for interactions with bupropion, diphenhydramine, and hydroxyzine resulting in severe hypertension and delirium. Among all cases studied, there were two deaths but the cause of death was not clearly linked to the drug interaction and in all other cases symptoms resolved within 10 days. Case reports described a washout period to avoid drug interactions and found persistent risk as distant as 18 days after withholding fluoxetine. A dose-response increased risk was not observed.

Conclusions from this paper are that the incidence of serotonin syndrome may be much lower than the previously estimated level of 25%. Linezolid associated serotonin syndrome appeared to have a low mortality but propensity and severity of the condition appeared multi-factorial and in some ways patient-specific, leading the authors to suggest clinicians should be familiar with signs of serotonin syndrome and educate their patients to report these early. Typical treatment for serotonin syndrome includes cyproheptadine or benzodiazepines. It is also noteworthy that phenytoin is not first line therapy for seizures in serotonin syndrome and propranolol is discouraged for treating hypertension as it may provoke shock from autonomic dysregulation.

Psychiatric medication use is common in the US population, and EPs should be aware of potential side effects of these drugs in both adults and children. Although EPs are unlikely to prescribe many of these medications directly, patients may present first to the ED with complications. A careful medication history and mindfulness of potential interactions with other drug classes, such as antibiotics, are important for patient safety and can minimize morbidity and mortality.