Antipsychotics and sudden death
It is well documented that the mortality rate in patients with schizophrenia is about twice as high as in the normal population and that the incidence of sudden death is significantly higher than in the normal population due to cardiovascular disease (Rusohena: 4.9 times higher than in the normal population). The causes of sudden death in these patients may be related to asphyxia, cardiovascular disorders, seizures, pulmonary thrombosis, allergies, and metabolic disorders, and often occur in young schizophrenic patients who are in good health. Most scholars believe that it may be related to antipsychotic medications, but it is not entirely clear in what aspect of the medication is responsible for sudden death. Wang Biao, Department of Psychiatry, Shanghai Mental Health Center
Mo dopamine in Israel i. Ilan et al. (2000) observed 5479 patients taking antipsychotics after 6 years and 8 months of administration and found that the incidence of sudden death was 3.8 times higher in patients using clozapine (561, or 10.24%) than in other antipsychotics. Sudden death in patients on clozapine occurred mostly in younger patients, on average 10.75 years younger than the age at which sudden death was caused by other drugs, and most of these patients were in significantly better physical condition than those treated with non-clozapine. Walker (1997) in the United States found 859 (12.8%) deaths in an analysis of 67,072 patients using clozapine, and although the mortality rate with clozapine was lower than with other drugs in his report, deaths due to pulmonary thrombosis and respiratory causes were about three times higher with clozapine than with other drugs. peacock & Gerlach (1994) also suggested that the cause of death may be related to pulmonary thrombosis. In addition, after an analysis of 12 papers on sudden death caused by clozapine alone and in combination since 1989, it was concluded that in combination, patients more often presented with delirium, changes in EEG, and increased salivation. The presence of the above conditions often has an impact on the timely diagnosis
Rapid increase of the dose (it is considered that the dose of clozapine should not exceed 125 mg/day in the first 2-3 weeks of treatment). Complementary intravenous administration of drugs such as Lore and chlorpromazine may lead to the development of sudden death.
Wayne A. Ray , Cecilia P. Chung (2009) et al. observed in a large controlled study in 44,218 and 46,089 patients taking classical versus non-classical antipsychotics, respectively, versus 186,600 normal population, appeared to have significantly higher sudden death due to cardiovascular disease than the normal group.
Factors of the environment.
Yosbl et al. reported that in high ozone areas, ozone increases the anticholinergic effects of clozapine and increases the occurrence of eosinophilia, which can lead to sudden death due to myocarditis, but this is only in high ozone areas such as Australia, and there are no controlled studies in low ozone areas. Therefore, this claim needs to be further confirmed.
Enzymatic factors.
Kilian et al. identified a specific group of individuals who were deficient in the enzymes CPY4501A2 and CPY4501A3, which are thought to affect the metabolism of clozapine, and because the metabolism is affected are highly susceptible to clozapine toxicity, which can lead to sudden death. In addition, the combination with fluvoxamine in SSIR should also be noted for changes in blood concentrations of clozapine.
Toxic effects on myocardium.
The direct toxic effects of antipsychotic drugs: direct inhibition of M2 receptors can produce toxic effects on myocardium, in addition, it has also been reported in the literature that high doses of antipsychotic drugs can directly cause inflammatory reactions in myocardial cells. Clinically, T-wave alterations, QT prolongation, and accelerated and abnormal heart rhythms can be observed, and in severe cases, malignant arrhythmias leading to sudden death can occur.
Asphyxia: Traditional antipsychotics due to their effects on the extravertebral
Pulmonary artery thrombosis.
Vandenbroucke et al. (1998) found in 14,000 autopsy reports from the Leiden University Medical Center from 1970-1994 that 10 of 27 patients who died from pulmonary thrombosis did so because of antipsychotic medication. walker (1997) found that 19 of 85,399 patients using clozapine Pulmonary artery thrombosis occurred in 19 of 85,399 patients using clozapine, 5.2 times more than with other drugs. In patients with sudden death from clozapine induced pulmonary thrombosis, autopsy reports often suggest that pulmonary artery thrombosis occurs in the branches of the pulmonary artery, and this phenomenon can be detected by CT in resuscitated patients. Regarding the mechanism of pulmonary artery thrombosis, Hagg et al. (2000) suggested that it may be related to three conditions: 1) the effect of antipsychotic drugs on platelets, causing platelet clotting; 2) an increase in anticardiolipid antibodies; and 3) the sedative effect of antipsychotic drugs, which often stagnates venous blood flow or patients with venous insufficiency. In addition, Hindersin et al. (1988) suggested that the increased secretion of adrenaline during the acute phase of psychiatric disorders may affect the coagulation system.2 Kilin et al. found that 7 out of 23 patients with pulmonary artery thrombosis may be related to myocarditis and cardiomyopathy. The EKG and echocardiogram usually do not reveal any abnormalities, so special attention should be paid to patients with heart valve disease, irregular heart rate, and a history of lower extremity surgery.
It is also believed that in patients with schizophrenia, such as those with prolonged bed rest, poor diet, obesity, too little exercise, and a history of intravenous use of other psychotropic drugs, they tend to be more susceptible to thromboembolic formation. In addition, because most of the above patients are admitted in a tense or rigid state, inappropriate use of ECT, with strong muscle contractions in the extremities, can often dislodge deep peripheral thrombus triggering pulmonary artery thrombosis, leading to sudden death.
Antipsychotics and antidepressants often cause postural hypotension, tachycardia, bradycardia, atrioventricular block, T-wave inversion, prolonged Q-Tc interval, and even torsional ventricular tachycardia, and this rhythm abnormality is one of the main causes of sudden death.
Among antipsychotics, those with a higher risk of QTc prolongation are methiodiazine, chlorpromazine, trifluoperazine, haloperidol, sertindole, clozapine, etc. Non-classical antipsychotics are less likely to cause QTc interval prolongation, but some studies have shown that ziprasidone, risperidone, olanzapine and haloperidol are more likely to cause QTc interval prolongation, so they have caused widespread concern in clinical applications.
The antidepressants amitriptyline, doxepin, desipramine, promethazine, and chlorpromazine have been shown to be associated with QT interval prolongation. Antidepressants prone to arrhythmias include the tricyclics (TCAs) amitriptyline, promethazine, chlorpromazine, doxepin, trimipramine, and nortriptyline, as well as the tetracyclic maprotiline. Maprotiline has less anticholinergic effects, but is difficult to rescue in the event of torsades de pointes (TdP) due to its long half-life (48h).
Tip-twisting ventricular tachycardia (TdP), referred to as tip-twisting ventricular tachycardia, is a special type of polymorphic tachyarrhythmia, with two clinical conditions: first, tip-twisting ventricular tachycardia with prolonged Q-T interval, of which a small proportion of tip-twisting ventricular tachycardia is atypical; second, tip-twisting ventricular tachycardia without prolonged Q-T interval. Most scholars refer to the former as “tip-twisting ventricular tachycardia” or “prolonged Q-T interval with polymorphic ventricular tachycardia” and the latter as “polymorphic ventricular tachycardia” because of the differences in pathogenesis and treatment. The latter is called “polymorphic ventricular tachycardia”. The latter is called “polymorphic ventricular tachycardia”. Patients with tip-twisting ventricular tachycardia have recurrent syncope and convulsions as the main clinical manifestations.
I. Etiology and pathogenesis
The torsional ventricular tachycardia with prolonged QT interval is often referred to as long QT syndrome (LQTS). Depending on the etiology, mode of origin and treatment, tip-torsional ventricular tachycardia is divided into congenital (adrenaline-dependent) and acquired (intermittent-dependent). Congenital Q-T interval syndrome with tip-twisting ventricular tachycardia is mostly epinephrine-dependent and is not described in this section because it is not associated with psychotropic drugs.
Acquired Q-T interval prolongation with tip-twist ventricular tachycardia This type is common and is mostly long interval dependent: causes include: slow heart rate due to organic heart disease such as myocardial ischemic heart disease, congestive heart failure, hypertrophic cardiomyopathy, myocarditis, Kawasaki syndrome, etc.; bradycardia, atrioventricular and sinus conduction block; electrolyte disturbances such as hypokalemia most commonly, hypocalcemia, hypomagnesemia; drug-related factors such as multiple drug interactions, inhibition and induction of cytochrome P450 enzymes, combination of drugs; liver damage, increasing age and female susceptibility; drug-induced such as antiarrhythmics, tricyclic antidepressants, antipsychotics (such as clozapine, chlorpromazine, methiodiazine and sulpiride), non-sedating antihistamines, macrolide antibiotics, antifungals, antimalarials, etc.
QT interval includes the process of ventricular depolarization (Q wave) and repolarization (T wave). the physiological heart rate increase in QT interval shortens the QT length, so it is expressed by QTc after correcting the heart rate factor. the QTc length is usually around 400ms, below 440ms is considered normal. the longer the interval, the greater the possibility of TdP, often using 500ms as the cut-off value. Drug-induced such as antiarrhythmics, tricyclic antidepressants, certain antipsychotics, non-sedating antihistamines, macrolide antibiotics, antifungals, and antimalarials can lead to prolonged QT intervals and/or drug-induced mainly due to drug-delayed ventricular repolarization, uneven velocity of ventricular muscle repolarization, and different conduction velocities, resulting in multiple foldback and causing episodes of TdP. Ventricular depolarization is the result of rapid inward flow of sodium ions selectively through sodium channels. Tricyclic antidepressants (TCAs) block sodium channels, slowing depolarization, widening QRS waves, and consequently prolonging QTc. Ventricular repolarization involves calcium, sodium, and some potassium channels, and the potassium channel Ikr plays a key role in drug-induced TdP. As an Ikr channel blocker, methiodiazide causes TdP and sudden death, in contrast to TCAs that block sodium channels. This suggests that methiodiazine is often associated with episodes of TdP and sudden death in comparison to TCAs, although both prolong QTc. The study suggests that QTc prolongation may be a warning for the occurrence of TdP.
II. Clinical manifestations
Torsional ventricular tachycardia often presents as recurrent and transient episodes that often cause vertigo and syncope due to the extremely rapid ventricular rate and the sharp decrease in cardiac output during the episode. The duration of syncope is consistent with the duration of the tachycardia attack, and the slower ventricular rate is easier to tolerate. The syncope often occurs at the beginning of the tachycardia, and later it may disappear temporarily despite the presence of the tachycardia. If the torsional ventricular tachycardia is not controlled in time, it can continue to recur and eventually turn into ventricular fibrillation and death.
Acquired Q-T interval prolongation with tip-twisting ventricular tachycardia (interval-dependent). Patients at high risk for this type of TdP are those with a history of TdP episodes, organic heart disease, bradycardia, use of drugs that prolong the QT interval, and hypokalemia or hypomagnesemia.
The ECG before the onset of TdP can be normal sinus rhythm or slow arrhythmias such as sinus bradycardia, junctional rhythm, high or complete AV block, or atrial fibrillation or other ectopic rhythms. The QT interval ≥0.6 seconds is a high-risk indicator that TdP will occur, and about 1M5TdP episodes are preceded by a QT interval <0.5 seconds; in about 95% of patients, the last supraventricular beat before the episode has a long R-R interval (long cycle), and the ventricular premature that triggers TdP falls on the Tu of the previous supraventricular or sinus beat (short cycle) This results in a special "short-long-short" ventricular tachycardia pattern.
The electrocardiogram of TdP episodes shows a series of widened ventricular wave groups with a frequency of 160-230 beats Min, averaging about 220 beats Min, and irregular rhythm, with temporal changes in the polarity and amplitude of the ventricular wave groups. The twisting pattern of the above ventricular tachycardia waveform may not be seen in all leads, so it is best to use simultaneous tracing of multiple leads to show this phenomenon. Each episode of tachycardia lasts from a few seconds to tens of seconds and can be terminated spontaneously, but it is very likely to recur. If left untreated, this recurrent process can continue and progress to ventricular fibrillation.
III. Diagnosis
ECG changes: QTc ≥ 480 ms, tip-twisting ventricular tachycardia, T-wave changes, 3-lead T-wave tangents, slow heart rate; clinical manifestations: syncope on exertion or non-exertion, clear family history of LQT, and unexplained sudden cardiogenic death in immediate family members aged < 30 years. The diagnosis of typical TdP is not difficult. The ECG during the attack shows a prolonged QT interval, and the ECG during the attack must be distinguished from general ventricular tachycardia or ventricular fibrillation: general ventricular tachycardia presents as a series of broad QRS wave clusters of almost constant morphology, with recognizable ST segments and T waves, and the attack often does not terminate on its own, and general ventricular tachycardia can also be induced by RonT ventricular premature, but the ventricular premature association interval is shorter. In ventricular fibrillation, wave clusters and ST and T waves are unrecognizable, and persistent episodes can lead to death.
The risk of pharmacogenic arrhythmia should be considered when the QTc interval rises 30-60 ms from the original base in individuals taking psychotropic drugs. interval less than 450ms is normal, 450-470ms is critical, and more than 470ms is prolonged QTc interval should be given sufficient attention. Psychiatric patients who show paroxysmal syncope, convulsions and corresponding changes in ECG during treatment should consider the possibility of TdP attack.
IV. Treatment
Treatment of intermittent dependent TdP
Discontinue the drugs that induce QT interval prolongation, correct electrolyte disturbances, and treat obvious bradycardia. Pharmacogenic QT prolongation and TdP treatment, antidepressants or antipsychotic drugs, and other drugs that may cause QTc prolongation should be discontinued immediately.
2. Increase the basal heart rate Atrial or ventricular pacing (≥110 beats/min), or intravenous isoproterenol or atropine injection (100 beats/min) are available. In patients with normal atrioventricular conduction, atrial pacing is best to minimize the difference in ventricular repolarization and shorten the QT interval, and to avoid stimulation of the ventricles due to ventricular cannulation. Isoprenaline: Shortens the QT interval and increases the basal heart rate, and reduces the difference in ventricular repolarization. The dose can be adjusted to maintain the ventricular rate at 90-110 beats/min by intravenous injection, and the dose must be closely observed and adjusted at any time during treatment. The presence of myocardial ischemia and hypertension are relative contraindications. Atropine has a similar effect, but the efficacy is not good, should not be applied continuously.
3. intravenous potassium and magnesium supplementation potassium ion and repolarization process is closely related, low potassium can make the cell membrane permeability to potassium decreased, repolarization delayed. Available potassium chloride intravenous drip, the total amount of potassium salt according to the degree of potassium deficiency. Although magnesium sulfate does not directly shorten the QT interval and affect the heart rate, but it can activate the ATPase on the cell membrane to homogenize repolarization, inhibit post-depolarization, change the non-response period and improve myocardial metabolism. It is effective for TdP with hypertension, heart failure and atrioventricular block, and especially suitable for those who are not suitable for isoproterenol and have no condition to regulate pacing. Add magnesium sulfate to glucose solution 40ml intravenous push, later can be maintained intravenously, to 3 ~ 20mg / min continuous sedation.
4. other Ⅰa, Ⅰc, Ⅲ antiarrhythmic drugs, forbidden quinidine, diisoproterenol, amiodarone, propafenone, verapamil and other drugs for the treatment of TdP. can try Ⅰb, such as lidocaine 1-3mg/kg intravenous. In case of persistent episodes of torsional ventricular tachycardia, treatment should be according to the principles of cardiac arrest, including chest compressions and artificial respiration, etc. For those with a tendency to ventricular fibrillation, electrical resuscitation can be used, but repeated electric shocks should be avoided because the electric shock itself can cause loss of myocardial potassium and aggravate the attack. For severe bradycardia and severe conduction block with recalcitrant episodes and contradictory medications, permanent pacemakers should be installed.
V. Prevention of pharmacogenic QT prolongation and TdP
Antidepressants and antipsychotics should be used with caution in patients with existing cardiovascular disease, especially in those with decompensated cardiac function; those with hypokalemia should be disabled in particular, and timely correction of hypokalemia or hypomagnesemia; for women, the elderly, and those with poor cardiac function and abnormal liver and kidney function, or those whose patients’ relatives have QT interval prolongation syndrome, newer antidepressants SSRIs, SNRIs with lower risk should be selected as far as possible, or non- At the same time, the evolution of their ECG should be observed in a timely manner, and once QTc prolongation is detected, or sudden unexplained syncope occurs, it is advisable to stop the drug immediately and take appropriate measures; avoid the combination of multiple drugs, especially the combination of other QT prolongation drugs or hepatic cytochrome P450CYP3A4 isoenzyme inhibitors.
Prevention
1. Patients with cardiac disorders should avoid taking psychotropic drugs that impair cardiac function during psychiatric treatment, or choose psychotropic drugs with mild side effects on the heart if treatment is required.
2. Patients should have their electrocardiograms and other relevant indicators tested regularly while taking medication, so that their family members can also understand the precautions for taking medication and observe any abnormalities in cardiac function together with the patient.
3. Elderly and frail patients should closely observe the reaction to the medication and inform the doctor promptly when they feel chest tightness or panic, and adjust the dose or change to other medications.
4. Patients who have been taking medication for a long time should not take the side effects lightly and should be carefully and continuously observed to detect early signs and treat them early.
In summary, although the efficacy of antipsychotic drugs for schizophrenia is well recognized, the serious adverse effects on patients should be taken seriously by physicians, especially in those with the following conditions
1. Patients with poor physical condition, such as chronic malnutrition, dehydration, or extreme euphoria.
2, accompanied by serious physical diseases, such as cardiovascular disease, pancreatitis and hepatobiliary disorders.
3.Suspected organic brain disease
4.Diabetes mellitus and other metabolic diseases
References
1, Rene Thomassen, Jan P. Vandenbroucke and Frits R. Rosendall Antipsychotic Medicatoin and Venous thrombosis British Journal of Psychiatry (2001), 179,63-64
2, Modai, Ilan MD; Hirschmann, Shmuel MD: Sudden Death in Patients Receiving Clozapine :A Preliminary Investigation Journal of Pschopharmocology Volume 20(3) June 2000 325-327
3, Gwen L Zornbeerg, Hershel Jick Antipsychotic drug use and risk of first-time idiopathic venous thromboemblism: a case- control study The Lancet. vol 356 October 7, 2000
4, Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. drugs 2002;62(11):1649-71.
5, Wayne A. Ray, Ph.D., Cecilia P. Chung, M.D., M.P.H., Katherine T. Murray, M.D., Kathi Hall, B.S., and C. Michael Stein, M.B., Ch.B. Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death N Engl J Med 2009; 360:225-235January 15, 2009