Sudden Death and Tricyclic Antidepressants: Clinical Considerations for Children

Popper, Charles W.; Elliott, Glen R.

doi:10.1089/cap.1990.1.125

Cited by 42 publications

(8 citation statements)

References 11 publications

(10 reference statements)

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“…(Table 1). While desipramine should be used with caution in prepubertal children (15), low-cost, clinically relevant antidepressants such as desipramine (1,3,4,17) and sertraline may restore the therapeutic efficacy of chloroquine against resistant parasites in vivo and thereby enhance the clinical utility of chloroquine against widespread drug-resistant P. falciparum.…”

mentioning

confidence: 99%

Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum

Coutaux¹,

Mooney²,

Wirth³

1994

Antimicrob Agents Chemother

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Chloroquine resistance in Plasmodiumfalciparum was reversed in vitro by the neuronal monoamine reuptake inhibitors and antidepressants desipramine, sertraline, fluoxetine, and norfluoxetine but not by carbamazepine, an antiseizure and mood-stabilizing tricyclic drug resembling desipramine which only weakly inhibits neuronal monoamine reuptake. These findings have important clinical implications for drug combination therapy.The goal of this work was to investigate the potential use of clinically relevant antidepressants as combination therapy with antimalarial drugs in drug-resistant malarial infections. Previous studies have shown that antidepressants such as desipramine, imipramine, protriptyline, nortriptyline, doxepin, and fluoxetine modify chloroquine resistance in Plasmodium falciparum in vitro (1, 4, 11). These tricyclic antidepressants and fluoxetine block the sodium-dependent neuronal reuptake of either norepinephrine or serotonin, and tricyclic antidepressants such as imipramine also block the H+-ATPase-regulated monoamine uptake by monoamine storage granules (5). More recently, it has been shown that the monoamine transport proteins in the neuronal plasma cell membrane (10, 18) and neuronal monoamine storage vesicles (10) belong to a superfamily of transport proteins with 12 transmembrane domains which also include the malaria parasite protein mdrl (7,19) and the P glycoprotein in tumor cells (9). In this article, we report that the two antidepressants and neuronal monoamine reuptake inhibitors sertraline and norfluoxetine modify antimalarial resistance to chloroquine in vitro; Taken together with previous studies (1, 4, 11), these findings suggest that antidepressants which act as neuronal monoamine reuptake inhibitors may also enhance the antimalarial activity of chloroquine against drug-resistant forms of P. falciparum.The organisms used in these studies were (i) the chloroquine-resistant clone W2 of P. falciparum from Indochina and (ii) the chloroquine-sensitive clone HB3 of P. falciparum from Honduras. We examined the reversal of chloroquine resistance in the W2 clone of P. falciparum by several neuronal monoamine reuptake inhibitors, namely, desipramine, fluoxetine, norfluoxetine, and sertraline. The monoamine reuptake inhibitors had intrinsic antimalarial activities only at very high concentrations. The IC50s obtained for the W2 clone for each drug are as follows: chloroquine, 65 ng/ml; desipramine, 2,770 ng/ml; fluoxetine, 2,455 ng/ml; norfluoxetine, 1,045 ng/ml; and sertraline, 1,458 ng/ml. The drug IC50s determined for the chloroquine-sensitive clone HB3 are as follows: chloroquine, 10 ng/ml;. desipramine, 4,000 ng/ml; and sertraline, 1,590 ng/ml.In Table 1, we present the response modification index (RMI) for each monoamine reuptake inhibitor, which reflects modulation of susceptibility to chloroquine in the presence of one of the monoamine reuptake inhibitors at predetermined concentrations. The RMI for each monoamine reuptake inhibitor decreased as the concentration of psychotropic drug wa...

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mentioning

confidence: 99%

Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum

Coutaux¹,

Mooney²,

Wirth³

1994

Antimicrob Agents Chemother

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“…[107,113] More disconcerting are the reports that have described unexplained sudden death being associated with desipramine. [122][123][124][125] Furthermore, the TCAs have a relatively low therapeutic index, [126] which is an important consideration when these medications are prescribed to children and adolescents at risk for surreptitious ingestion because of suicidality. When compared with the newer antidepressants, the TCAs are associated with a higher risk of death due to overdose.…”

Section: Adverse Effectsmentioning

confidence: 99%

Pharmacological Treatment of Depression in Children and Adolescents

1999

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Major depression is a common disorder during childhood and adolescence. Over the past decade, many new antidepressants have been marketed in the US. In adults, these newer agents have been shown to be as effective as the prototypic tricyclic antidepressants (TCAs). Further, when compared with the TCAs these medications are better tolerated and are safer in overdose. Although TCAs are effective in the treatment of depressed adults, controlled clinical trials have not demonstrated their efficacy in either children or adolescents. In addition, concerns about the safety of TCAs and the monoamine oxidase inhibitors has left disappointingly few pharmacological treatment options available for depressed children and adolescents. For this reason, clinicians have begun to prescribe the newer agents for this population, despite the fact that relatively little is known about their disposition, safety or effectiveness in the young. Investigators have begun to examine whether the use of newer antidepressant medications such as fluoxetine, sertraline, paroxetine, fluvoxamine, nefazodone, and venlafaxine is truly indicated for children and adolescents with major depression. Pharmacokinetic studies of sertraline, paroxetine and nefazodone have been performed in depressed youths. The results of these studies have provided data for rational administration strategies for these agents. They have also provided evidence that these agents may be well tolerated in children and adolescents. Further evidence that these agents are often well tolerated when prescribed to depressed youths has been obtained from both open-label and double-blind studies. Published studies have generally shown that open-label treatment with these newer agents often leads to symptom amelioration in paediatric patients with major depression. Since high rates of placebo response are often seen in depressed children and adolescents, results from these studies cannot be interpreted to suggest that these medications have true antidepressant efficacy in this population. At present, the results of only two such studies have been published. The results of one of these trials are difficult to interpret because of methodological considerations. The other study reported that treatment with fluoxetine was superior to placebo. This paper critically reviews what has been published about the pharmacological treatment of depressed paediatric patients and provides some guidance to the use of antidepressants in this patient population, paying particular attention to what is known about the newer antidepressants as well as considering directions for future research.

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“…Numerous articles have been published regarding this topic. [12][13][14][15][16][17][18][19][20][21][22][23][24] While additional data have been reported there remains considerable controversy regarding this question. It has been a subject of intense debate and many outstanding questions remain.…”

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confidence: 99%

Sudden Death Related to Selected Tricyclic Antidepressants in Children

Varley

2001

Paediatric Drugs

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The association between tricyclic antidepressant (TCA) use in children and increased risk of sudden death is unclear, but still possible. There are suitable alternatives to TCAs for all of the indications in which they have shown efficacy. A prudent practice model for the utilisation of TCAs has been developed. This includes initial utilisation of alternative agents, with TCAs as secondary or tertiary choices; informed consent from patient and family, including mention of the possible relationship of TCA with sudden death; vigilance of the emerging literature; and finally, systematic monitoring of patients, including electrocardiograms, drug serum concentrations and vital signs. This protocol needs to be validated with regard to utility and the degree of assistance it provides in the management of children treated with TCAs.

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Sudden Death and Tricyclic Antidepressants: Clinical Considerations for Children

Cited by 42 publications

References 11 publications

Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum

Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum

Pharmacological Treatment of Depression in Children and Adolescents

Sudden Death Related to Selected Tricyclic Antidepressants in Children

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