Clomipramine toxicity

GRAPEFRUIT JUICE CLOMIPRAMINE T risk of clomipramine toxicity. Not known whether T plasma concentration is sustained Clomipramine metabolism involves several CYP isoenzymes (e.g. CYP1A2, CYP3A4, i CYP2D6) Be aware... 

Treatment with imipramine, the most studied TCA, leaves 45% to 70% of patients panic free. Both desipramine and clomipramine have demonstrated effectiveness in PD as well. Despite their efficacy, TCAs are considered second- or third-line pharmacotherapy due to poorer tolerability and toxicity on overdose.48,49 TCAs are associated with a greater rate of discontinuation from treatment than SSRIs.53 PD patients taking TCAs may experience anticholinergic effects, orthostatic hypotension, sweating, sleep disturbances, dizziness, fatigue, sexual dysfunction, and weight gain. Stimulant-like side effects occur in up to 40% of patients.49... 

Rao et al.20 demonstrated a fluorescence polarization immunoassay for evaluating serum concentrations of tricyclic antidepressants (amitriptyline, imipramine, clomipramine, and doxepin) with respect to nonresponse, compliance, therapeutic window, and influences of age, sex, substance abuse, and toxicity. Abbott Laboratories TDx/TDxFLx Toxicology Tricyclic Assay FPIA (fluorescence polarization immunoassay) was used. This assay of 50 /uL samples contained tricyclic antidepressant antibodies raised in rabbits and fluorescein-labeled tricyclic antidepressant as a tracer. The assay was calibrated with imipramine in the range of 75 to 1000 fig/L (268 to 3571 nmol/L). Intra-assay and inter-assay coefficients of variation for internal quality control samples from the manufacturer were 4.2 and 4.7%, respectively. The limits of detection were 72,71,64, and 72 nmol/L for amitriptyline, imipramine, clomipramine, and doxepin, respectively. This high-throughput immunoassay was easy to use although amitriptyline, dosulepine, desipramine, and nortriptyline showed cross-reactivities ranging from 74 to 100%. 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

All SSRIs have an antipanic effect. Their advantages are limited adverse effects and lack of toxicity. Because of more acceptable adverse effect profiles, the SSRIs are usually the drugs of choice. Several studies consistently indicate that SSRIs such as fluoxetine, sertraline, paroxetine, fluvoxamine, as well as agents such as clomipramine and trazodone, all possess antipanic efficacy, although the last may be less effective than imipramine ( 24, 105, 106, 107, 108 and 109). 

The latter action is responsible for the serious CNS and cardiac toxicity (e.g., delirium, seizures, cardiac arrhythmias, and cardiac arrest) that can occur at high plasma drug concentrations of clomipramine just as with any TCA. These effects are problematic with adults and may be of even greater concern with children and adolescents. 

For these reasons, TDM can serve several roles when using clomipramine. First, it can be used to determine whether clomipramine or its demethlylated metabolite constitutes the majority of the circulating drug. Second, TDM can be used to guide dose adjustment to ensure plasma concentrations equivalent to those seen in adults whose OCD is successfully treated. This approach also ensures that concentration levels do not approach or exceed the toxic threshold for TCAs (i.e., greater than 450 ng/mL). Like adults, children and adolescents demonstrate a wide variability in their capacity to metabolize TCAs. As mentioned earlier, children are usually faster metabolizers of these drugs than adults, so they typically need doses of approximately 2.5 to 3.5 mg/kg. Once puberty has been reached, the required doses can be reduced by as much as 50%. 

Imipramine Mixed and variable blockade of NET and SERT Like SNRIs plus significant blockade of autonomic nervous system and histamine receptors Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine) Long half-lives CYP substrates active metabolites Toxicity Anticholinergic, G.-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Interactions CYP inducers and inhibitors... 

The tricyclics, such as clomipramine (Anafranil), amitriptyline (Elavil), and imipramine (Tofranil), have been used for several decades. I have previously described their central nervous system toxic effects in some detail (Breggin, 1983b see also Breggin, 1991b). This section will therefore be abbreviated. A list of some of the older antidepressants can be found in the appendix. 

Overdose of moclobemide by itself rarely appears to give rise to serious problems. This is in contrast to overdose with conventional monoamine oxidase inhibitors, which can cause fatal 5HT toxicity. However, if patients take moclobemide together with serotonergic antidepressants, such as SSRIs or clomipramine, 5HT toxicity is common. 5HT toxicity occurred in 11 of 21 patients who took overdoses of moclobemide and serotonergic agents but in only one of 33 patients who took moclobemide alone (13). Consistent with this, four patients died, presumably of 5HT toxicity, after co-ingesting 3,4-methyle-nedioxymethamphetamine (MDMA, ecstasy) and moclobemide (14). 

In a controlled comparison between clomipramine and amitriptyline, the former caused adverse effects more often, especially drowsiness (3). Overdose toxicity is the same as with other tricyclic antidepressants (4) fatal interactions with monoamine oxidase (MAO) inhibitors have been reported (SEDA-18, 16 5). Altogether, toxic effects are not substantially different. 

FLECAINIDE TCAs Risk of arrhythmias Additive effect both drugs may be proarrhythmogenic. In addition, amitriptyline and clomipramine may inhibit CYP2D6-mediated metabolism of flecainide Monitor PR, BP, and ECG closely watch for flecainide toxicity... 

MAOIs TCAs-AMITRIPTYLINE CLOMIPRAMINE DESIPRAMINE IMIPRAMINE NORTRIPTYLINE t risk of stroke, hyperpyrexia and convulsions, t plasma concentrations of TCAs, with risk of toxic effects, t risk of serotonin syndrome and of adrenergic syndrome with older MAOIs. Clomipramine may trigger acute confusion in Parkinson s disease when used with selegiline TCAs are believed to also act by inhibiting the reuptake of serotonin and norepinephrine, increasing the risk of serotonin and adrenergic syndromes. The combination of TCAs and antidepressants can t risk of seizures Very hazardous interaction. Avoid concurrent use and consider the use of an alternative antidepressant. Be aware that seizures occur with overdose of TCAs just before cardiac arrest... 

CLOMIPRAMINE MODAFINIL Variable effect on clomipramine CYP2C19 provides an ancillary pathway for the metabolism of clomipramine. Modafinil inhibits CYP2C19 reversibly at pharmacologically relevant concentrations. Modafinil also induces CYP1A2 Watch for both poor response and early features of toxicity of clomipramine... 

TCAs DRUG DEPENDENCE THERAPIES-BUPROPION 1. t risk of seizures This risk is marked in elderly people, in patients with a history of seizures, addiction to opiates/cocaine/ stimulants, and in diabetics treated with oral hypoglycaemics or insulin 2. t plasma concentrations of amitriptyline, clomipramine, desipramine, doxepin and imipramine, with risk of toxic effects 1. Bupropion is associated with a dose-related risk of seizures. TCAs lower the seizure threshold. Additive effects when combined 2. Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 1. Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in those with severe hepatic cirrhosis) 2. Initiate therapy of these drugs at the lowest effective dose... 

Toxicity. Toxic effects have been associated with blood concentrations greater than 0.4pg/ml of clomipramine plus monodesmethylclomipramine. 

Overdose. Depression is a risk factor for both parasuicide and completed suicide, and TCAs are commonly taken by those who deliberately self-harm. Dothiepin (dosulepin) and amitriptyline are particularly toxic in overdose, being responsible for up to 300 deaths per year in the UK despite the many alternative antidepressants that are available. Lofepramine is at least 15 times less likely to cause death from overdose clomipramine and imipramine occupy intermediate positions. 

Rare Hepatic toxicity tinnitus bone marrow depression, including agranulocytosis seizures peripheral neuropathy severe cardiovascular effects in patients with cardiac disease photosensitivity dysarthria smttering withdrawal symptoms nausea, tremor, anorgasmia, and seizures may be more common with clomipramine tardive dyskinesia and neuroleptic malignant syndrome with amoxapine renal failure with overdosage of amoxapine... 

Co-administration is usually safe and effective, although rare cases of serotonin syndrome are documented. Amitriptyline and nortriptyline are safer than clomipramine, desipramine, or imipramine. Clomipramine should be avoided. Additive toxicity is rare, and could be evidenced by hyperpyrexia, convulsions, cardiac collapse, and death. No significant interactions were found with amitriptyline or desipramine and moclobemide. 

The ability to drive, to handle dangerous machineiy or to do other tasks requiring complex psychomotor skills may be impaired by amitriptyline, and to a lesser extent by doxepin or imipramine, particularly during the first few days of treatment This impairment can be increased by alcohol Amoxapine, clomipramine, desipramine, and nortriptyline appear to interact with alcohol only minimally. Information about other tricyclics appears to be lacking, although most manufacturers of tricyclics warn that the effects of alcohol may be enhanced. There is also evidence that alcoholics (without liver disease) may need larger doses of desipramine and imipramine to control depression. However, the toxicity of some tricyclics may be increased by alcohol, and in alcoholics with liver disease. 

Studies in subjects with blood-alcohol levels of 40 to 60 mg% found that clomipramine had only slight or no effects on various choice reaction, coordination, memory and learning tests. A case describes a fatal poisoning in a chronic alcoholic patient taking clomipramine for depression. The ultimate toxic effect was thought to be due to alcohol-induced decreased biotransformation of clomipramine, as post-mortem examination revealed toxic liver damage, and low levels of the metabolite were found in blood and hair samples. ... 

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