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Selective acquired long QT syndrome (saLQTS) upon risperidone treatment.

Lazarczyk MJ, Bhuiyan ZA, Perrin N, Giannakopoulos P - BMC Psychiatry (2012)

Bottom Line: On the other hand, the patient did not respond with QT prolongation to some other antipsychotics.In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length.Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of General Psychiatry, University Hospitals of Geneva and Faculty of Medicine of the University of Geneva, 1202 Geneva, Switzerland. maciej.lazarczyk@hcuge.ch

ABSTRACT

Background: Numerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially.

Case presentation: We report here a case of aLQTS in response to small doses of risperidone that was confirmed at three independent drug challenges in the absence of other QT-prolonging drugs. On the other hand, the patient did not respond with QT prolongation to some other antipsychotics. In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length. A detailed genetic analysis revealed no mutations or polymorphisms in KCNH2, KCNE1, KCNE2, SCN5A and KCNQ1 genes.

Conclusions: Our observation suggests that some patients may display a selective aLQTS to a single antipsychotic, without a potassium channel-related genetic substrate. Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

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Related in: MedlinePlus

A. Risperidone induces QT prolongation. ECG at the admission was normal and the corrected QT value (QTc; according to the Bazett formula) was not prolonged under the treatment of aripiprazol (20 mg/day), haloperidol (3 mg/day) and escitalopram (20 mg/day). Subsequently, the QTc value was monitored regularly. At day 4, 9 and 15 risperidone (2 x 1 mg/day) was introduced and thereafter rapidly stopped at day 4, 10 or 15, respectively, as indicated on the graph. Other antipsychotics/antidepressant were discontinued, as indicated on the graph. QTc prolongation was observed each time when risperidone was introduced, even after a single 1 mg dose, and it returned to the normal range immediately after the risperidone treatment was stopped. B. Comparative analysis of the impact of risperidone and clozapine on QT length. QTc values have been measured during the treatment with progressively increasing doses of clozapine (12,5 – 275 mg; n=14), risperidone (1 – 2 mg; n=3) or in the absence of these drugs (control; n=8). Risperidone but not clozapine caused statistically significant QTc prolongation in this patient, as assessed by Mann–Whitney U test. NS – statistically not significant. C. Plasma concentration of aripiprazol, clozapine and risperidone in relation to KCNH2 IC50. Drug plasma concentration has been determined at the steady state, for aripiprazol and clozapine, or the second day after its introduction, for risperidone (2 x 1 mg/day), at the time of the predicted peak of the plasma drug level. On the graph, the drug concentrations have been expressed as a fold of their respective KCNH2 IC50values (263 nM for aripiprazol, 320 nM for clozapine, and 148 nM for risperidone), previously determined for these drugs. At the indicated concentrations, risperidone, but not aripiprazol or clozapine, significantly prolonged QT length.
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Figure 1: A. Risperidone induces QT prolongation. ECG at the admission was normal and the corrected QT value (QTc; according to the Bazett formula) was not prolonged under the treatment of aripiprazol (20 mg/day), haloperidol (3 mg/day) and escitalopram (20 mg/day). Subsequently, the QTc value was monitored regularly. At day 4, 9 and 15 risperidone (2 x 1 mg/day) was introduced and thereafter rapidly stopped at day 4, 10 or 15, respectively, as indicated on the graph. Other antipsychotics/antidepressant were discontinued, as indicated on the graph. QTc prolongation was observed each time when risperidone was introduced, even after a single 1 mg dose, and it returned to the normal range immediately after the risperidone treatment was stopped. B. Comparative analysis of the impact of risperidone and clozapine on QT length. QTc values have been measured during the treatment with progressively increasing doses of clozapine (12,5 – 275 mg; n=14), risperidone (1 – 2 mg; n=3) or in the absence of these drugs (control; n=8). Risperidone but not clozapine caused statistically significant QTc prolongation in this patient, as assessed by Mann–Whitney U test. NS – statistically not significant. C. Plasma concentration of aripiprazol, clozapine and risperidone in relation to KCNH2 IC50. Drug plasma concentration has been determined at the steady state, for aripiprazol and clozapine, or the second day after its introduction, for risperidone (2 x 1 mg/day), at the time of the predicted peak of the plasma drug level. On the graph, the drug concentrations have been expressed as a fold of their respective KCNH2 IC50values (263 nM for aripiprazol, 320 nM for clozapine, and 148 nM for risperidone), previously determined for these drugs. At the indicated concentrations, risperidone, but not aripiprazol or clozapine, significantly prolonged QT length.

Mentions: We report here a case of 37-year old woman with schizophrenia, hospitalized for an exacerbation of psychotic symptoms. She had no personal/family history of cardiac diseases or sudden deaths. Besides benzodiazepines, she was treated at the admission with aripiprazol (20 mg/day), haloperidol (3 mg/day) and escitalopram (20 mg/day). The routine laboratory and clinical check-up (including ECG and blood electrolytes) revealed no abnormalities. The patient developed the aLQTS in response to small doses of risperidone (1–2 mg/day), confirmed at three independent drug challenges. Noteworthy, the patient responded with significant QT prolongation to risperidone (QTc increase from 458 to 508 ms), also when all other drugs, which might potentially affect QT length, were discontinued (Figure 1A). The reason of this extreme sensitivity to risperidone was unclear but the contribution of a cytochrome polymorphism or other elimination failures is unlikely since risperidone prolonged QT at very low blood concentrations (19.1 nM). Moreover, the concentration of paliperidone, an active metabolite of risperidone with QT-prolonging potential [8], was very low too, and the cumulative blood concentration of risperidone and paliperidone was subtherapeutic. Interestingly, the patient did not respond with QT prolongation following the administration of other antipsychotics (e.g. aripiprazol, clothiapine, haloperidol; data not depicted). In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone [9], had no effect on QT-length (Figure 1B).


Selective acquired long QT syndrome (saLQTS) upon risperidone treatment.

Lazarczyk MJ, Bhuiyan ZA, Perrin N, Giannakopoulos P - BMC Psychiatry (2012)

A. Risperidone induces QT prolongation. ECG at the admission was normal and the corrected QT value (QTc; according to the Bazett formula) was not prolonged under the treatment of aripiprazol (20 mg/day), haloperidol (3 mg/day) and escitalopram (20 mg/day). Subsequently, the QTc value was monitored regularly. At day 4, 9 and 15 risperidone (2 x 1 mg/day) was introduced and thereafter rapidly stopped at day 4, 10 or 15, respectively, as indicated on the graph. Other antipsychotics/antidepressant were discontinued, as indicated on the graph. QTc prolongation was observed each time when risperidone was introduced, even after a single 1 mg dose, and it returned to the normal range immediately after the risperidone treatment was stopped. B. Comparative analysis of the impact of risperidone and clozapine on QT length. QTc values have been measured during the treatment with progressively increasing doses of clozapine (12,5 – 275 mg; n=14), risperidone (1 – 2 mg; n=3) or in the absence of these drugs (control; n=8). Risperidone but not clozapine caused statistically significant QTc prolongation in this patient, as assessed by Mann–Whitney U test. NS – statistically not significant. C. Plasma concentration of aripiprazol, clozapine and risperidone in relation to KCNH2 IC50. Drug plasma concentration has been determined at the steady state, for aripiprazol and clozapine, or the second day after its introduction, for risperidone (2 x 1 mg/day), at the time of the predicted peak of the plasma drug level. On the graph, the drug concentrations have been expressed as a fold of their respective KCNH2 IC50values (263 nM for aripiprazol, 320 nM for clozapine, and 148 nM for risperidone), previously determined for these drugs. At the indicated concentrations, risperidone, but not aripiprazol or clozapine, significantly prolonged QT length.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3539970&req=5

Figure 1: A. Risperidone induces QT prolongation. ECG at the admission was normal and the corrected QT value (QTc; according to the Bazett formula) was not prolonged under the treatment of aripiprazol (20 mg/day), haloperidol (3 mg/day) and escitalopram (20 mg/day). Subsequently, the QTc value was monitored regularly. At day 4, 9 and 15 risperidone (2 x 1 mg/day) was introduced and thereafter rapidly stopped at day 4, 10 or 15, respectively, as indicated on the graph. Other antipsychotics/antidepressant were discontinued, as indicated on the graph. QTc prolongation was observed each time when risperidone was introduced, even after a single 1 mg dose, and it returned to the normal range immediately after the risperidone treatment was stopped. B. Comparative analysis of the impact of risperidone and clozapine on QT length. QTc values have been measured during the treatment with progressively increasing doses of clozapine (12,5 – 275 mg; n=14), risperidone (1 – 2 mg; n=3) or in the absence of these drugs (control; n=8). Risperidone but not clozapine caused statistically significant QTc prolongation in this patient, as assessed by Mann–Whitney U test. NS – statistically not significant. C. Plasma concentration of aripiprazol, clozapine and risperidone in relation to KCNH2 IC50. Drug plasma concentration has been determined at the steady state, for aripiprazol and clozapine, or the second day after its introduction, for risperidone (2 x 1 mg/day), at the time of the predicted peak of the plasma drug level. On the graph, the drug concentrations have been expressed as a fold of their respective KCNH2 IC50values (263 nM for aripiprazol, 320 nM for clozapine, and 148 nM for risperidone), previously determined for these drugs. At the indicated concentrations, risperidone, but not aripiprazol or clozapine, significantly prolonged QT length.
Mentions: We report here a case of 37-year old woman with schizophrenia, hospitalized for an exacerbation of psychotic symptoms. She had no personal/family history of cardiac diseases or sudden deaths. Besides benzodiazepines, she was treated at the admission with aripiprazol (20 mg/day), haloperidol (3 mg/day) and escitalopram (20 mg/day). The routine laboratory and clinical check-up (including ECG and blood electrolytes) revealed no abnormalities. The patient developed the aLQTS in response to small doses of risperidone (1–2 mg/day), confirmed at three independent drug challenges. Noteworthy, the patient responded with significant QT prolongation to risperidone (QTc increase from 458 to 508 ms), also when all other drugs, which might potentially affect QT length, were discontinued (Figure 1A). The reason of this extreme sensitivity to risperidone was unclear but the contribution of a cytochrome polymorphism or other elimination failures is unlikely since risperidone prolonged QT at very low blood concentrations (19.1 nM). Moreover, the concentration of paliperidone, an active metabolite of risperidone with QT-prolonging potential [8], was very low too, and the cumulative blood concentration of risperidone and paliperidone was subtherapeutic. Interestingly, the patient did not respond with QT prolongation following the administration of other antipsychotics (e.g. aripiprazol, clothiapine, haloperidol; data not depicted). In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone [9], had no effect on QT-length (Figure 1B).

Bottom Line: On the other hand, the patient did not respond with QT prolongation to some other antipsychotics.In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length.Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of General Psychiatry, University Hospitals of Geneva and Faculty of Medicine of the University of Geneva, 1202 Geneva, Switzerland. maciej.lazarczyk@hcuge.ch

ABSTRACT

Background: Numerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially.

Case presentation: We report here a case of aLQTS in response to small doses of risperidone that was confirmed at three independent drug challenges in the absence of other QT-prolonging drugs. On the other hand, the patient did not respond with QT prolongation to some other antipsychotics. In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length. A detailed genetic analysis revealed no mutations or polymorphisms in KCNH2, KCNE1, KCNE2, SCN5A and KCNQ1 genes.

Conclusions: Our observation suggests that some patients may display a selective aLQTS to a single antipsychotic, without a potassium channel-related genetic substrate. Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

Show MeSH
Related in: MedlinePlus