Pharmacogenomics and tailored polypharmacy: an 80-year-old lady with rosuvastatin-associated rhabdomyolysis and maprotiline-related Ogilvie's syndrome
.

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.
.

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.

Maprotiline treatment in depression. A perspective on seizures.

Eleven McLean Hospital (Belmont, Mass) depressed patients who experienced seizures while receiving maprotiline hydrochloride are presented, as are data on 87 cases reported to the manufacturer (Ciba-Geigy). Most seizures occurred at high dosages, sometimes after many weeks at a stable dose, but neither rapid dosage escalation nor high drug plasma levels seemed related to seizure occurrence. Our experience suggests that a long-acting metabolite might be responsible for seizures. Ten of the 11 McLean Hospital seizures occurred in patients receiving dosages outside of the since-revised current dosage guidelines, as did 60% of the seizures reported to the company. Data in this study suggest that reductions in maximum dosage of maprotiline prescribed after the initial six weeks of treatment could result in a further decrease in risk of seizures beyond that obtained from previous alterations in regimens.

Plasma free 3-methoxy-4-hydroxyphenylglycol predicts response to fluoxetine.

This study was designed to investigate the relationship between platelet serotonin (5-HT) and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) measures in depressed outpatients obtained from the same patient with unipolar depression during the pretreatment period and subsequent response to 6 weeks of treatment with either fluoxetine or maprotiline. Compared to the nonresponder group, the fluoxetine responders showed significantly higher pretreatment levels of MHPG, but no difference in pretreatment 5-HT levels. There were no significant differences in either 5-HT or MHPG levels between maprotiline responders and nonresponders. As to posttreatment levels, there were no between-group differences in 5-HT or MHPG between responders and nonresponders to either fluoxetine or maprotiline. When the relationships between changes in 5-HT or MHPG levels and treatment response were examined, 5-HT values showed a marked decrease in both fluoxetine responders and nonresponders, but no significant changes were found in the maprotiline treatment groups. On the other hand, MHPG levels in the fluoxetine nonresponders tended to increase (borderline significance), whereas the MHPG levels for fluoxetine responders and maprotiline responders and nonresponders were unaffected from pre- to posttreatment. Pretreatment levels of plasma free MHPG appear to predict response to fluoxetine.

Adverse cutaneous reactions to antidepressants.

The authors review the literature on adverse cutaneous reactions to antidepressant medications. The prevalence of rashes ranges from approximately 2% to 4% but is higher for certain antidepressants such as maprotiline and carbamazepine. Antidepressant drug reactions result in a variety of cutaneous morphologic patterns, but the majority of eruptions are exanthematous. The patterns of these reactions are similar whether the pathogenesis is mediated by immunologic or nonimmunologic mechanisms. The management of patients with adverse cutaneous reactions to antidepressants is discussed, and various recommendations are given.

Incidence of seizures with tricyclic and tetracyclic antidepressants.

One hundred eighty-six depressed psychiatric inpatients were seen at our institution during 1982. Forty-five of these patients were treated with tricyclic antidepressants, 32 received maprotiline hydrochloride, a tetracyclic compound, 20 received other medications, and 82 received no drug treatment. One patient in the tricyclic group (2.2%) and five patients in the maprotiline group (15.6%) developed seizures. In four patients the seizure followed the institution of maprotiline therapy by less than three weeks. These data indicate that depressed patients taking the tetracyclic drug maprotiline are at risk for developing epileptic seizures.

Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial.

Amitriptyline (AT) relieves some patients with postherpetic neuralgia (PHN). Many patients suffer side effects and better therapies are necessary. The aim of this study was to evaluate the efficacy of maprotiline (MT) (noradrenergic) compared to AT (mixed noradrenergic and serotonergic) in this disorder. Thirty-five patients entered a randomized, double-blind, crossover trial of these two agents. We found that MT relieved PHN in many patients but was not as effective as AT. Side effects were troublesome with both agents. Relief of steady pain, brief pain and pain on tactile stimulation occurred. Four groups of responses were identified. Some patients reported relief with both agents, some with neither agent and others with only one of the drugs. Most patients were not depressed and analgesia was observed to occur without change in depression ratings in most patients who responded. This result provides evidence that in some patients AT may act via a selective noradrenergic mechanism in relieving PHN and that individuals may differ in the balance and type of neurotransmitters inhibiting pain. Selective noradrenergic agents may be effective if AT fails.

Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity.

To understand the relative efficacy of noradrenergic and serotonergic antidepressants as analgesics in chronic back pain without depression, we conducted a randomized, double-blind, placebo-control head-to-head comparison of maprotiline (a norepinephrine reuptake blocker) and paroxetine (a serotonin reuptake blocker) in 103 patients with chronic low back pain. Of these 74 completed the trial; of the 29 who did not complete, 19 were withdrawn because of adverse effects. The intervention consisted of an 8-week course of maprotiline (up to 150 mg daily) or paroxetine (up to 30 mg daily) or an active placebo, diphenhydramine hydrochloride (up to 37.5 mg daily). Patients were excluded for current major depression. Reduction in pain intensity (Descriptor Differential Scale scores) was significantly greater for study completers randomized to maprotiline compared to placebo (P=0.023), and to paroxetine (P=0.013), with a reduction of pain by 45% compared to 27% on placebo and 26% on paroxetine. These results suggest that at standard dosages noradrenergic agents may provide more effective analgesia in back pain than do selective serotonergic reuptake inhibitors.

The serotonin reuptake inhibitor paroxetin is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome.

Recent studies indicate that antidepressant drugs with potent serotonin reuptake inhibiting properties are effective in reducing the symptoms of premenstrual syndrome (PMS). In order to elucidate whether all antidepressant drugs are equally effective in the treatment of PMS or whether potent serotonin reuptake inhibition is a prerequisite for reducing premenstrual complaints, women suffering from severe PMS were treated daily for three menstrual cycles with a selective serotonin reuptake inhibitor, paroxetine (n = 22), or with a selective noradrenaline reuptake inhibitor, maprotiline (n = 21); in addition, a placebo group was included (n = 22). Six symptoms (irritability, depressed mood, tension/anxiety, increased appetite/craving for carbohydrates, bloating, and breast tenderness) were rated by the participants daily throughout the study. With respect to all outcome measurements, the symptom reduction obtained with paroxetine was significantly superior to that obtained with placebo; with respect to irritability, increased appetite/carbohydrate craving, bloating, and breast tenderness, as well as global self-rating, paroxetine was significantly superior also to maprotiline. The clear-cut superiority of paroxetine over maprotiline indicates that not all antidepressant drugs are equally effective in the treatment of PMS; rather, like panic disorder and obsessive compulsive disorder, but in contrast to depression, PMS apparently responds better to serotonin reuptake inhibitors than to antidepressants with a noradrenergic profile.

Q-T prolongation and torsades de pointes ventricular tachycardia produced by the tetracyclic antidepressant agent maprotiline.

Tricyclic antidepressant drugs such as imipramine and desipramine have long been known to produce cardiovascular side effects including sinus tachycardia, prolongation of the P-R, QRS, and Q-T intervals, and decreased T-wave amplitude. Life-threatening ventricular ectopic activity has occurred after tricyclic drug overdose. Recently, maprotiline (Ludiomil), a tetracyclic anthracene-derivative antidepressant, has become available for the treatment of affective disorders. It appears as effective as the tricyclic drugs in relieving unipolar depression. Although several studies have reported a low incidence of cardiovascular side effects, others show little difference between the tetracyclic and tricyclic drugs. This report describes a patient in whom maprotiline treatment caused Q-T prolongation and life-threatening torsades de pointes ventricular tachycardia (VT).

A comparison in rabbit isolated hearts of the dysrhythmogenic potential of amitriptyline, maprotiline and mianserin in relation to their ability to block noradrenaline uptake.

1. In isolated hearts of rabbits, perfusion with (-)-noradrenaline (0.0059 to 5.9 micronM) resulted in chronotropic and inotropic responses and a shortening of the interval between peak atrial and peak ventricular tensions (the A-V contraction interval). No dysrhythmias developed but at higher concentrations (590 micronM) 2 out of 7 hearts developed dysrhythmias (extrasystoles). 2. Perfusion with the antidepressants amitriptyline or maprotiline (4.8 micronM) or mianserin (28.8 micronM) reduced ventricular force, did not change heart rate and only amitriptyline reduced atrial force and lengthened the A-V contraction interval. At 4.8 micronM mianserin produced only a marginal shortening of the A-V contraction interval. 3. At these concentrations no dysrhythmias developed but at higher concentrations (amitriptyline 8 micronM, maprotiline 8 micronM, mianserin 60 micronM) all the agents produced dysrhythmias involving an interference with atrio-ventricular synchronization. 4. In the presence of mianserin (4.8 micronM) perfusion with noradrenaline (0.0059 to 5.9 micronM) shortened the A-V contraction interval and did not produce dysrhythmias. In the presence of amitriptyline or maprotiline (4.8 micronM) or mianserin (28.8 micronM) the A-V contraction interval generally lengthened and most hearts developed dysrhythmias (usually involving interference with atrio-ventricular synchronization). 5. [3H]-(-)-Noradrenaline uptake in perfused rabbit hearts and in mouse isolated atria or vasa deferentia was inhibited by the antidepressants to a similar extent, amitriptyline being marginally most potent (molar potency taken as 1.0), maprotiline being less potent (1.5) and mianserin least potent (2.0)). 6. It is concluded that of these three antidepressants, mianserin is least cardiotoxic in this preparation and that the ability of these antidepressants to predispose to noradrenaline-induced dysrhythmias is not related to blockade of noradrenaline uptake.

Atrial flutter and maprotiline: case report.

Atrial flutter developed in an 80-year-old woman after 10 days of treatment with maprotiline at therapeutic concentrations. This cardiac irregularity is extremely rare with the conventional antidepressants. Evidence is reviewed to suggest that the likely mechanism was reuptake blockade of noradrenergic amines stimulating reentrant excitation within the atria.

Antidepressants and myoclonus: case report.

Myoclonus is a movement disorder of various etiologies. An alteration in CNS serotonin activity is hypothesized to be the underlying mechanism for several myoclonic syndromes. Myoclonus has been reported as a side effect of antidepressants, and the serotonin hypothesis has been advanced to include this syndrome. A case is reported of myoclonus induced by an antidepressant purported to have no effect on serotonin activity.

Hepatotoxicity associated with maprotiline therapy: case report.

The author reports a case of markedly elevated liver enzymes associated with maprotiline therapy for depression. The patient was cachexic but was anicteric and had no evidence of viral hepatitis. The serum enzyme levels returned to normal shortly after the medication was discontinued.

Therapeutic superiority of maprotiline versus doxepin in geriatric depression.

In a double-blind study, 49 geriatric patients suffering from primary major depression were treated with maprotiline or doxepin. Efficacy and safety were assessed by the Hamilton Depression Rating Scale and the Zung Self-Rating Depression and Anxiety scales, side effects profile, routine laboratory tests, and measurements of blood levels. Although marked improvement was obtained with both antidepressants, patients on maprotiline showed statistically greater improvement than those on doxepin. No significant differences were detected between the two drugs with respect to side effects. A significant positive correlation was obtained between dosage and blood levels of maprotiline and doxepin, but there was no correlation between blood levels and clinical response. Overall, results suggest that maprotiline may be superior to doxepin in the treatment of geriatric depression.

Maprotiline and seizures.

Maprotiline has been reported to be less likely to cause epileptic seizures than the tricyclic antidepressants. The authors describe two cases in which patients suffered their first epileptic attacks while on therapeutic doses of maprotiline. They recommend that the newer antidepressants, as well as the tricyclics, should not be used with the aliphatic neuroleptics because of a possible additive or synergistic epileptic effect. If patients are to be withdrawn from C.N.S. depressants, then this should be accomplished prior to initiation of antidepressant therapy. Patients who are predisposed to seizures should have lower initial doses of antidepressants.

Review of the cardiovascular effects of heterocyclic antidepressants.

We review the effects of heterocyclic antidepressant compounds on the cardiovascular system. It has been shown that tricyclic antidepressants (TCAs) slow intraventricular conduction, and this can be seen on a standard ECG as the increased QRS, PR, and QTc intervals. This prolonged conduction is dangerous to patients in two conditions. In overdose, delayed conduction may lead to a complete heart block or ventricular reentry arrhythmias. Either of these complications, or a combination of both, may lead to death. When treated with TCAs at therapeutic plasma levels, depressed patients with preexisting conduction disease, particularly bundle-branch block, are at higher risk to develop symptomatic A-V block than depressed patients free of conduction disorders. Clinically, the effects of TCAs on conduction does not differ significantly within the family of drugs. Who gets complications is much more a function of severity of the patient's preexisting cardiac condition. The most common cardiovascular effect of TCAs is orthostatic hypotension. Postural hypotension is more dangerous in elderly patients because it may lead to falls that cause serious physical injuries. Severe orthostatic hypotension is more likely to develop in depressed patients with left ventricular impairment and/or in patients taking other drugs like diuretics or vasodilators. Nortriptyline has been shown to cause significantly less serious postural blood pressure drops, an important difference between this drug and other TCAs. Another cardiovascular effect of TCAs is that they reduce ventricular arrhythmias. They share this property with Type 1A antiarrhythmic compounds, and a variety of Type 1 antiarrhythmics have recently been shown to increase mortality in postmyocardial infarction patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The new generation antidepressants: promising innovations or disappointments?

"New generation" antidepressants are generally considered to include all agents introduced in recent years which are neither tricyclic in structure nor monoamine oxidase inhibitors. They include the tetracyclics (mianserin and maprotiline), the bicyclic serotonergic compounds (fluoxetine and citalopram), and the unicyclics (bupropion), as well as the triazolobenzodiazepine derivatives (alprazolam), the triazolopyridines (trazodone) and the tetrahydroisoquinolines (nomifensine). Methodologic and economic considerations have hampered attempts to develop agents with significantly greater specificity or safety than traditional agents. Traditional agents, while lacking specificity, do have extensive records of efficacy and long-term safety and are usually less expensive than new agents. Patients not responding to traditional agents often have medical or characterologic problems that exclude them from participating in controlled studies of new agents. These problems are discussed and potential approaches to the development of new agents are presented.