Pharmacogenomics and tailored polypharmacy: an 80-year-old lady with rosuvastatin-associated rhabdomyolysis and maprotiline-related Ogilvie's syndrome
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What is known and objectives: Multiple adverse drug reactions (ADRs) are expected, and thus should be prevented in the elderly comorbid patient on polypharmacy. Rosuvastatin is commonly prescribed for the treatment and prevention of atherosclerotic diseases, and in rare cases, is associated with rhabdomyolysis. Maprotiline is a tetracyclic antidepressant, infrequently used in the United States, but seemingly more broadly in European countries. Acute colonic pseudo-obstruction (Ogilvie's syndrome) caused by maprotiline has thus far, to our knowledge, not yet been described in the literature. CASE SUMMARY: We present a unique case of synchronous rhabdomyolysis and Ogilvie's syndrome in an 80-year-old lung cancer survivor following a recent ischemic stroke for which she was prescribed clopidogrel and rosuvastatin for secondary prevention, and maprotiline for post-stroke, new-onset insomnia and anxiety. The ADRs resolved on removal of the offending agents and initiation of conservative treatment. Retrospective pharmacogenetic testing of the patient's drug-metabolizing enzymes and transporters was performed to guide further management and prevent future potential drug interactions and ADRs. What is novel and conclusions: This is an interesting, albeit unfortunate, complex case that depicts the risk of rare adverse effects to medications and their potential relationship to pharmacogenetics. The impact of anticholinergic side effects of antidepressants on gastrointestinal motility, risk of myopathies with statins, increased susceptibility to ADRs caused by drug-drug interactions, and the utility of pharmacogenomic testing are discussed. The question whether commercially available pharmacogenomic tools are relevant for everyday use to direct patient care and reduce harmful drug-drug interactions is addressed and warrants further research.
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Gallbladder emptying in patients with major depression: a case series.

INTRODUCTION: Although several adverse effects of antidepressants on the gastrointestinal tract have been described (bleeding, constipation, dolichocolon), their influence on gallbladder motility was not investigated.The aim of our study was to investigate the effects of selected antidepressants on gallbladder emptying in patients with major depression. METHODS: The study was set up as an open clinical trial, with the same intervention (ingestion of test meal provoking gallbladder emptying) undertaken in 112 patients with major depression. There were 30 patients not taking antidepressants (the control group), 25 patients taking amitriptyline, 30 patients taking maprotiline, and 27 patients taking fluoxetine. The volume of gallbladder in the study patients was measured by ultrasonography before the test meal, and 15, 30, 45 and 60 min after the meal. RESULTS: 1 h after ingestion of the study meal, the amitriptyline group showed incomplete gallbladder emptying (F=10.829, df=3, p=0.000; mean residual volume 11.0±6.1 mL), while in the control, maprotiline and fluoxetine groups emptying of gallbladder was complete (mean residual volumes 5.0±3.3 mL, 5.6±3.7 mL and 5.7±2.3 mL, respectively). DISCUSSION: In patients with cholecystitis, it would be wise to use antidepressants which do not impair gallbladder emptying, like maprotiline or fluoxetine, and to avoid amitriptyline.

Comparisons of glucose-insulin homeostasis following maprotiline and fluoxetine treatment in depressed males.

BACKGROUND: To investigate the effects of antidepressants on glucose-insulin homeostasis, we provided homogenous situation and performed standard procedures to assess the interactions of antidepressants and glucose regulation during hospitalization. METHODS: Twenty-three non-diabetic depressed males were recruited and assigned to two groups based on the antidepressants received (maprotiline n=11, fluoxetine n=12). The severity of depression was evaluated using a 21-item Hamilton depression rating scale (HAM-D). Before and after the 4-week treatment, participants underwent 75-g oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (SI), glucose effectiveness (SG), acute insulin response (AIR), and disposition index (DI) were estimated using minimal model method. RESULTS: The HAM-D scores were reduced significantly (P<0.005) after antidepressant treatment. Following maprotiline treatment, the body weight and BMI were significantly increased (P=0.02). Individuals treated with maprotiline displayed a significantly increased AIR (3239+/-682 vs. 4698+/-597 pmol; P=0.04) during the FSIGT. LIMITATIONS: The sample size was limited. Furthermore, the study was conducted in the early phase of depression-treated course. CONCLUSIONS: The results suggest that the beta-cell function is hyperbolic in order to offset the insulin resistance following maprotiline treatment. Our findings imply that norepinephrine reuptake inhibitor (NRI) antidepressants might attenuate insulin sensitivity.

Tricyclic antidepressants, QT interval prolongation, and torsade de pointes.

The authors postulate mechanisms linking tricyclic antidepressants, QT interval prolongation, torsade de pointes, and sudden cardiac death. Case reports identify amitriptyline and maprotiline as the tricyclic antidepressants most likely to provoke torsade de pointes. Risk factors of family history of congenital long QT syndrome, age, female sex, metabolic and cardiovascular disease, metabolic inhibitors, hypokalemia, drug overdose, and co-prescription of drugs associated with QT interval prolongation were found in cases of torsade de pointes associated with tricyclic antidepressants. Clinicians should be cautious when prescribing tricyclic antidepressants with other drugs, such as thioridazine, that are capable of prolonging the QT interval.

[Current views on migraine and anti-migraine preparations]. / Sovremennye predstavleniia o migreni i mekhanizmakh deistviia sredstv dlia ee lecheniia i profilaktiki.

On the basis of comprehensive experimental and clinical research the authors defined a variety of migraine-related mechanisms and schemes of migraine-correction by drugs, which should be both of the vascular- and general-actions to ensure an effective medication.

Chronic treatment with antidepressants decreases intraoperative core hypothermia.

UNLABELLED: We investigated temperature regulation during anesthesia and postoperative shivering in chronically depressed patients given antidepressant drugs. We studied 35 depressed patients and 35 control patients who underwent orthopedic surgery. Tympanic membrane temperatures 60, 75, and 90 min after induction in the depression group were significantly (P < 0.05) higher than those of the control group. There were no significant differences in mean skin temperature between the depression and the control groups. Eight of 35 patients in the depression group and 2 of 35 patients in the control group developed postanesthetic shivering. The incidence of shivering in the depression group was significantly more frequent than that in the control group (P = 0.04). The tympanic membrane temperature of the patients treated with clomipramine tended to be higher than that of the patients treated with maprotiline. In conclusion, intraoperative core hypothermia in chronically depressed patients was decreased. However, the incidence of shivering in depressed patients was significantly more frequent. IMPLICATIONS: Thermoregulation in chronically depressed patients is often altered. The alteration of body temperature is affected by depression itself and by antidepressants. General anesthesia has an influence on thermoregulatory control. However, temperature regulation during anesthesia in chronically depressed patients remains unclear.

[QT prolongation and torsade de pointes tachycardia during therapy with maprotiline. Differential diagnostic and therapeutic aspects]. / QT-Verlängerung und Torsade de pointes-Tachykardie bei Therapie mit Maprotilin. Differenzialdiagnostische und -therapeutische Aspekte.

HISTORY AND ADMISSION FINDINGS: A 69-year-old somnolent woman developed severe heart failure, aggravated by recurrent episodes of ventricular tachycardia. The patient showed central and peripheral edema. 24 hours earlier, she had suffered cerebral seizures that were successfully terminated by phenytoin. For 13 years, persistent atrial fibrillation had been frequency-controlled with antiarrhythmic drugs (verapamil and glycosides) and treated by oral anticoagulation. In addition, there had been long-term anti-depressant therapy with the tetracyclic agent maprotiline. INVESTIGATIONS: Torsade de pointes tachycardia was documented in the electrocardiograms. In addition, the QT interval was extensively prolonged (QTc = 0.70 sec). Neither electrolyte disturbances nor acute cardiac ischemia were seen. Echocardiography revealed a highly reduced ejection fraction of 25 % and a moderately dilated left ventricle. Angiography showed a collateralized occlusion of the right and plaques of the left coronary artery. TREATMENT AND COURSE: Repeated torsade de pointes tachycardia resulted in hemodynamic compromise and were terminated by defibrillations. After intravenous magnesium and xylocaine administration as well as with termination of maprotiline and antiarrhythmic co-medication, QT prolongation decreased. In addition, the recurrent torsade de pointes tachycardia stopped. Subsequently, however, there were several bradycardia episodes, QT duration remained long. Accordingly, a VVI pacemaker was implanted. Up to now, the patient is doing well. CONCLUSIONS: With antidepressant therapy, a risky constellation including comorbidity and interactions with potentially arrhythmogenic drugs may lead to QT prolongation. Medication that delays conduction or causes bradycardia may generally favour torsade de pointes tachycardia. In case of indispensable multi-drug therapy, regular clinical as well as electrocardiographic monitoring with special emphasis on QT interval is mandatory.

Bilateral angle closure glaucoma and visual loss precipitated by antidepressant and antianxiety agents in a patient with depression.

A 71-year-old woman with depression had been treated with an antidepressant (maprotiline) and antianxiety agents (clotiazepam and alprazolam). She had previously complained of ocular pain and blurred vision. However, thorough ocular examination was not performed at those times. On examination, visual acuity was no light perception OD and hand motion OS. Intraocular pressures were 33 mm Hg OU. Moderately dilated pupils, atrophic irises, shallow anterior chambers and closed angles were seen in both eyes. Despite treatment, her visual acuity decreased to no light perception bilaterally. Psychiatrists and ophthalmologists should be aware that antidepressants and antianxiety agents can precipitate angle closure glaucoma in susceptible eyes.

Is selectivity for serotonin uptake associated with a reduced emergence of manic episodes in depressed patients?

To determine whether selectivity for serotonin reuptake plays a role in antidepressant-associated mania (AAM), we evaluated the frequency of treatment-emergent mania in patients with unipolar depression who received either citalopram, a highly selective serotonin uptake inhibitor, or the adrenergic tetracyclic antidepressants (TTCAs) maproriline and mianserin, or placebo. Data were collected from post-marketing reports of adverse events, three placebo-controlled trials and four double-blind comparative trials. Of the total 4,004 depressed patients treated with citalopram (2482 from postmarketing data, 840 from placebo-controlled studies and 682 from TTCAs comparative studies), 25 (0.62%) had manic episodes. The rate of AAM in the comparative trials was significantly lower in the citalopram-treated patients (1/682, 0.15%) than in the TTCA-treated patients (5/389, 1.29%) (P = 0.03). In the placebo-controlled studies, no manic episodes were reported in the patients given placebo, but one manic episode occurred in a citalopram-treated patient (1/840, 0.12%). The citalopram-treated patients in whom AAM developed were significantly older than those in whom it did not (about 10 years, P < 0.001); gender distribution was similar. In conclusion, despite its limitations, our study apparently indicates that citalopram, a highly selective serotonin reuptake inhibitor, is associated with a significantly lower rate of treatment-emergent manic episodes than TTCAs, which have noradrenergic activity, but a similar rate to that reported for less selective SSRIs.

Visual perseveration: a new side effect of maprotiline.

OBJECTIVE: The aim of this paper is to describe a case of visual perseveration including palinopsia during maprotiline therapy. METHOD: A single case report. RESULTS: The patient, a 56-year-old depressive man, suffered from visual perseveration during maprotiline therapy. The visual perseveration was dose-related and disappeared with reduction and cessation of the therapy. CONCLUSION: The present findings suggest that maprotiline can induce visual perseveration including palinopsia in some patients.

Prolonged stationary colonic motility recording in seven patients with severe constipation secondary to antidepressants.

The aim of this study was to determine whether the colonic motor profile of seven patients with constipation secondary to antidepressants differed from the motility of seven patients with idiopathic constipation and seven healthy volunteers. All constipated patients had very severe constipation. Colonic manometric recordings were performed for 24 h. The number of high amplitude propagating contractions (HAPC) was lower in the two groups of constipated patients than in controls. No HAPC were observed in 5/7 patients with constipation secondary to antidepressants and in 1/7 patients with idiopathic constipation. The overall area under the curve (AUC) in the left colon was lower in the two constipated patient groups than in controls. AUC increased after a 1000-kcal standard meal given at noon in controls but not in the two groups of constipated patients. In conclusion, in patients with constipation secondary to antidepressants, the overall AUC was as poor as in patients with idiopathic constipation, and no colonic response to eating was observed. Moreover, the number of HAPC was more markedly decreased in patients with constipation secondary to antidepressants than in patients with idiopathic constipation.

Antidepressant drugs and seizure susceptibility: from in vitro data to clinical practice.

The use of antidepressant drugs (ADs) in patients with epilepsy still raises uncertainties because of the widespread conviction that this class of drugs facilitates seizures. A detailed knowledge of this issue in its various aspects may help in optimal management of patients suffering concurrently from epilepsy and depression. This article reviews the available data in vitro in animals and humans concerning the known potential of various ADs to induce epileptic seizures. Emphasis has been placed on those variables that may generate confusion in interpreting the results of the various studies. Most ADs at therapeutic dosages exhibit in nonepileptic patients a seizure risk close to that reported for the first spontaneous seizure in the general population (i.e., <0.1%). In patients taking high AD doses, seizure incidence rises markedly and may reach values up to 40%. With a patient history of epilepsy and/or concomitant drugs that act on neuronal excitability, low or therapeutic AD doses may be sufficient to trigger seizures. Experimental data are in partial conflict with human data on the relative potential seizure risk of the various ADs. Therefore, a reliable scale for assigning a relative value to an individual AD or to single AD classes cannot be made. It appears fair to say that maprotiline and amoxapine exhibit the greatest seizure risk, whereas trazodone, fluoxetine, and fluvoxamine exhibit the least. Some ADs may also display antiepileptic effects, especially in low doses, in experimental models of epilepsy and in humans, but the mechanism of this action is largely unknown. The available data suggest that ADs may display both convulsant and anticonvulsant effects and that the most important factor in determining the direction of a given compound in terms of excitation/inhibition is drug dosage. It is probable that drugs that increase serotonergic transmission are less convulsant or, even, more anticonvulsant than others. Because of mutual pharmacokinetic interactions between antiepileptic drugs and ADs, with consequent marked changes in plasma concentrations, it remains to be established whether or not plasma AD levels that are effective against depression also facilitate seizures. Finally, exploring the mechanisms through which ADs modulate neuronal excitability might open new possibilities in antiepileptic drug development.