A poster that was presented at the Annual APA conference in Y2019 - San Francisco

1. P8-163 Drug-Induced Brugada Syndrome in a Middle-Aged Female Patient:
Drugs, EKG Diagnosis, Electrophysiology, & Surveillance Recommendations
Frank W Meissner, MD, RDMS, RCDS; Cynthia Garza, JD, MD; Sarah L. Martin, MD
Texas Tech University Health Sciences Center at El Paso - Department of Psychiatry
Abstract
Screening of EKG's prior to initiation of psychopharmacological drug therapy for underlying QTc prolongation
is a routine best practice. However, Brugada syndrome, a loss-of-function mutation of the SCN5A gene which
encodes for the voltage-gated cardiac sodium channel responsible for the generation of the rapid upstroke of
the myocardial action potential is a rare but important cause of sudden cardiac death (SCD). Brugada-induced
SCD is characterized by ventricular fibrillation and the EKG pattern of ST-segment elevation in leads V1–V3
(unrelated to ischemia, electrolyte abnormalities, or structural heart disease) while distinctive ( right bundle
branch block [RBBB] pattern with ≥2-mm coved ST-segment elevation in the right precordial leads), is largely
unknown to practicing Psychiatrists. Its clinical importance relates to the high rate of ventricular fibrillation
(13% in a recent review) treated with offending drugs, as well as the inability to detect pre-exposure EKG
predictive markers on baseline EKG necessitating serial EKG surveillance. A 48-year-old Caucasian female on
Amitriptyline/Fluoxetine for more than 5 years had an unremarkable baseline EKG 15 April 2013. She presented
for evaluation of dizziness. EKG demonstrated Type 1 Brugada Syndrome, with PR prolongation (218 msec)
and with uncharacteristic but extreme QTc prolongation (548 msec). Her psychopharmacological drug therapy
had been unchanged for years. Discontinuation of Amitriptyline resulted in some improvement in the EKG
pattern at 24 hours, but a demonstration of drug-induced Brugada pattern mandated ICD implantation. The
most recent review identified 74 cases of Brugada syndrome induced by non-cardiac drugs occurring in 62
reports. The duration of the exposure of the majority of cases was weeks to years. The most frequently
reported oral agents were lithium and amitriptyline accounting for 20% and 16% of cases respectively. The
case highlights the following points: 1. Drug-Induced Brugada Syndrome while rare, has a high risk of SCD. 2.
Baseline EKG analysis is insensitive for detection of a patient’s increased risks for Drug-induced Brugada
syndrome 3. Consequently, serial EKG evaluation at 1 month, 3 months, 6 months and annually thereafter
when the patient is on a drug known to result in Drug-induced Brugada syndrome is a reasonable follow-up
plan.
A 48 year-old Caucasian female with long standing chronic pain and depression was placed on simultaneous Fluoxetine and Amitriptyline therapies. Five
years after the beginning of this therapy she was seen in the Emergency Department complaining of multiple episodes of transient dizziness, lasting
variously from seconds to < 1 minute, that first occurred 24 hours prior to her ED evaluation. She denied true syncope or pounding or non-pounding
palpitations. No neurological symptoms other than transient and fleeting dizziness. She had no past cardiac history. Her baseline EKG is shown in Figure
1. Her psychiatric history was remarkable for a turbulent clinical course with multiple admissions until she was placed on the combination therapy
detailed above, with her last psychiatric hospitalization occurring > 6 years from the date of her ED evaluation. Her past medical history was remarkable
for the absence of any cardiac history, cardiac hospitalizations, cardiac symptoms or cardiac procedures. Her general physical examination and her
physical cardiological examination were entirely normal. A point of care cardiac ultrasound was done at the bed side and it showed an entirely normal
structural echocardiography examination. During her evaluation she was found to have EKG changes demonstrated in Figure 2. She was admitted to
telemetry, and her Amitriptyline was discontinued. She was seen by cardiology and had a single lead ICD implanted the day after admission. She was
discharged home to the usual care of her established psychiatrist.
Non-drug induced Brugada syndrome (BrS) usually becomes apparent in adulthood, although it can develop any time throughout life. Signs and
symptoms related to arrhythmias, including sudden death, can occur from early infancy to late adulthood. Sudden death typically occurs around age 40.
This condition may explain some cases of sudden infant death syndrome (SIDS). SIDS is characterized by sudden and unexplained death, usually during
sleep. Sudden unexplained nocturnal death syndrome (SUNDS) is a condition characterized by unexpected cardiac arrest in young adults, usually at night
during sleep. This condition was originally described in Southeast Asian populations, where it is a major cause of death. Recently it has been determined
that SUNDS and BrS are the same disorder.
Cardiac arrest may result from seemingly innocuous medications that do not necessarily have cardiac indications. The best-known example is the drug-
induced long QT syndrome. A less known but not necessarily less important form of drug-induced proarrhythmia is the drug-induced BrS. Brugada
syndrome is rare and has been a clinically diagnosable entity since 1992. It is virtually unknown to Psychiatrists. The website
http://www.BrugadaDrugs.org has up-to-date and free access to a consensus statement on the safe use of drugs in BrS. (see below for psychiatric drugs)
Psychotropic drugs to be avoided by patients with known Brugada Syndrome Psychotropic drugs preferably avoided by patients with known Brugada Syndrome
Recommendation class: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear; Recommendation class: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear;
Class IIb: conflicting evidence/opinion; Class III: very little evidence. Class IIb: conflicting evidence/opinion; Class III: very little evidence.
Case Report
The EKG diagnosis of Type I Brugada Syndrome is distinctive and is well illustrated in Figure 2, specifically, diagnosis is based solely on a specific but labile pattern on an
electrocardiogram (ECG), defined as a ≥ 0.2 mV coved-type ST-segment elevation in the right precordial leads. However, the ECG can be silent, requiring sodium blockers to unmask the
pathology. Identification of BrS patients is crucial to avoid sudden cardiac death (SCD), which is often the first symptom of the disease. Other troubling EKG patterns but not
immediately diagnostic of BrS are illustrated in Figure 3. (1) Type I pattern( ≥2-mm coved-type ST elevation in at least 1precordial lead) ; (2) type II pattern (≥2-mm saddleback ST
elevation in ≥ 1 right precordial lead) ; (3) type III pattern (ST elevation of < 2 mm in ≥1 precordial lead) further classified
as IIIC or IIIS when the ST elevation has coved or saddleback morphology. The most commonly mutated gene in this
condition is SCN5A , which is altered in approximately 30% of affected individuals. This gene encodes for
the Ina sodium channel, activation of which results in phase-zero depolarization of the cardiac myocyte.
Loss of function mutation of SCN5A alters the structure and function of the channel, reducing inflow of sodium ions into cells. (Figure4).
In some cases, certain drugs may cause an acquired Figure 3. BrS Patterns
form of the disorder. Drugs that can induce BrS include some
antiarrhythmics, anti-anginal agents, antihypertensive agents,
and psychiatric medications of several types and classes
(see lists to the left side of the poster).
In addition, hypercalcemia or hyperkalemia or hypokalemia have
been associated with acquired Brugada syndrome.
Additonally to causing a nongenetic form of this disorder,
these factors may trigger symptoms in people with an underlying
mutation in SCN5A.
In a recent review of drug induced Brugada syndrome1, the authors identified 74 cases of BrS induced by 27 noncardiac drugs
in 62 reports. Among these cases, 36 (49%) were induced by psychotropic drugs, 20 (27%) were induced by
analgesic–anesthetic drugs, and 18 (24%) were induced by other noncardiac drugs.
The most frequently reported agent was intravenous propofol, which accounted for 20% of cases. The most frequently
reported oral agents were lithium and amitriptyline (accounting for 20% and 16% of cases caused by oral drugs, respectively).
VF or pulseless VT was documented in 19 patients (26%), all but 5 of male gender. Monomorphic VT occurred in
4 additional patients(5%) leading to 23 patients with VT/VF.
Twenty-two patients had cardiac arrest and 10 of them died, resulting in a 13.5% mortality rate. Among 42 drug-induced BrS cases related to an orally administrated drug, the authors
knew the duration of exposure for 22. In the majority, the duration of exposure was weeks to years, whereas only 5 cases (23%) had been treated for < 72 hours. Thus, as in this case, the
majority of cases in which BrS was expressed, immediate or short term exposure EKG’s would have failed to establish the diagnosis.
In a separate report, long-term use of nortriptyline is associated with a 5-fold increased risk of sudden death, probably caused, at least in part, by drug- induced BrS.2
1. Drug-Induced Brugada Syndrome while rare, has a high risk of SCD.
2. Baseline EKG analysis is insensitive for detection of a patient’s increased risk for Drug-induced Brugada syndrome.
3. Serial EKG evaluation at 1 month, 3 months, 6 months and annually thereafter when the patient is on a drug known to result in Drug-induced Brugada syndrome is a
defensible follow-up plan.
1. Konigstein et al. Drug-induced Brugada syndrome: Clinical characteristics and risk factors. Heart Rhythm, Vol 13, No 5, May 2016. 1083-1087.
2. Bardai A, Amin AS, Blom MT, et al. Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability : evidence from bench, bedside, and community.
Eur Heart J 2013; 34: 1506–1516.
3. Wilde AA, Amin AS. Clinical Spectrum of SCN5A Mutations. ACC: Clinical Electrophysiology. 4(5), 2 0 1 8. 569-79.
Discussion
Conclusion
Figure 1: Baseline EKG – Pre-exposure to Amitriptyline/Fluoxetine
which fails to demonstrate any evidence of Brugada Syndrome
Generic Brand Use Class
Amitriptyline
Elavil®
Sarotex®
Tryptizol®
Antidepressive
(Tricyclic) IIa
Clomipramine Anafranil®
Anafril®
Antidepressive
(Tricyclic) IIa
Lithium Eskalith® Mood Stabilizer IIb
Loxapine Cloxazepine®Loxita
nee®
Antipsychotic IIa
Oxcarbazepine Trileptal® Anti-epileptic IIa
Nortriptyline Nortrilren®
Pamelor®
Antidepressive
(Tricyclic)
IIa
Desipramiine Norpramine®
Pentofranr®
Antidepressive
(Tricyclic)
IIa
Trifluoperazine Fluoperazine®
Stelazine®
Antipsychotic
(Phenothiazine)
IIa
Generic Brand Use Class
Bupropion/Maprotiline
Amfebutamone®/Aplenzin
®
(Wellbutrin®)/Deprilept®
Antidepressive
(Unicyclic)(Tetracyclic) IIb
Carbamazepine/Phenytoin/
Lamotrigine
Carbatrol®/Tegretol®
Dilantin®/Lamictal®
Anticonvulsant Agent
IIb
Clothiapine/Thioridazine Clotiapine®/Entumin®
Mellaril®
Antipsychotic IIb
Cyamemazine/Perphenazine Cianatil®/Perphenan® Antidepressive
Phenothiazine
IIb
Dosulepine,Imipramine Dothiepin®/Prothiaden®
Tofranil®
Antidepressive
(Tricyclic)
IIb
Doxepin Sinequan®
Zonalon®
Antidepressive
(Tricyclic)
IIb
Fluoxetine, Paroxetine,
Fluvoxamine
Prozac®/Sarafem®Paxil
®, Luvox®
Antidepressive
(SSRI)
IIb
Figure 4. Molecular Biology and Cellular Electrophysiology of Brugada Syndrome 3
References
Figure 2: Follow-up EKG – Post-exposure (5 years of therapy) to
Amitriptyline/Fluoxetine - classical changes of Type I Brugada Syndrome