Drug extrapyramidal side-effects or not: is there a dextromethorphan phenotype difference?

A recent hypothesis suggests the possible role of cytochrome P450 2D6 (CYP2D6) polymorphism (involved in the metabolism of a large number of drugs), as a potential risk factor for the development of extrapyramidal side-effects of psychotropic drugs. The CYP2D6 metabolizer phenotype (dextromethorphan test) of 31 drug treated psychiatric adult patients suffering from extrapyramidal side-effects (group 1) and of 31 matched patients without drug side effects (group 2) were compared. In the first group, 13 poor metabolizer patients (41.9 per cent) were found, characterized by a dextromethorphan metabolic ratio > 0.3, and only two patients in the second group (6.4 per cent). These data provide some support for the notion that in subjects in whom CYP2D6 is probably saturated, the risk of drug extrapyramidal side-effects may be increased. In such patients the choice of psychotropic drugs 'without' this risk must be preferred.

[Extrapyramidal side effects of neuroleptic and antidepressant treatment: assessment of potential risk factors through CYP2D6 genetic polymorphism]. / Effets indésirables extrapyramidaux des neuroleptiques et antidépresseurs--recherche de facteurs de risque: rôle du polymorphisme génétique du CYP2D6.

The objective of this study was to assign metabolizer phenotype (cytochrome P450 2D6 or CYP2D6) to drug treated psychiatric adult patients to assess if the CYP2D6 polymorphism could be a potential risk factor for the development of extrapyramidal side effects of psychotropic drugs. Twenty-eight unrelated in-patients (16 men and 12 women) treated with antidepressants and/or antipsychotic drug were phenotyped using dextromethorphan. Two groups of patients were considered depending on the presence (n = 14) or not (n = 14) of extrapyramidal side effects. The mean dextromethorphan/dextrorphan metabolic ratio (log10) did not differ between the two groups of patients (-1.13 +/- 0.9 and -1.56 +/- 0.5, NS). But significantly more patients with extrapyramidal side effects (n = 4) than patients without side effects (n = 0) were poor metabolizers. This result could be due to a quantitative difference between the 2 groups of drug treatment cosegregated with dextromethorphan, but several authors reported that extrapyramidal side effects seemed not to be always related to high plasma drug levels. So the authors concluded that the 2D6 polymorphism could be a risk factor of poor neurologic tolerance of psychotropic drugs, but not only through pharmacokinetic consequences. CYP 2D6 is indeed expressed in brain and seems to interfer with the metabolism of dopamine and other related neurotransmitters.

Citalopram: an interaction study with clomipramine in a patient heterozygous for CYP2D6 genotype.

A pharmacokinetic interaction between the selective serotonin reuptake inhibitor citalopram and a tricyclic antidepressant, clomipramine, was noted in a patient treated for major depression and obsessive-compulsive disorder. After the addition of citalopram, a desmethylclomipramine plasma level increase and an 8-hydroacy-desmethylclomipramine plasma level decrease were observed. The CYP2D6 phenotype, determined when the patient received the antidepressant comedication, characterized a poor metabolizer status (dextromethorphan metabolic ratio >0.3), despite a heterozygous genotype containing a wild-type allele with extensive metabolic capacity and a mutant non-functional allele (CYP2D6*1A/CYP2D6*4A). This case seems to be one of the first descriptions of the clinical relevance of a CYP2D6 heterozygous genotype in a patient treated with antidepressant.

[Clinical tolerance of a new antidepressant -- milnacipran]. / Tolérance clinique d'un nouvel antidépresseur, le milnacipran.

Milnacipran is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake with a good safety and tolerability profile. The efficacy and tolerance profile of this antidepressant have been compared with those of tricyclic and selective serotonin reuptake inhibitor antidepressants (SSRIs) in open-label and placebo-controlled trials. But no data in clinical practice are available. The authors studied the tolerability of milnacipran (100 to 200 mg/d) in 28 depressed inpatients receiving usual comedications during a mean period of 33 days (3 to 107 days). The incidence of adverse events was determined with the help of the Pharmacovigilance Center of the Centre Hospitalo-Universitaire (Besançon, France). Among the 28 patients, milnacipran was well tolerated by 18 of them. Side-effects were noted in 10 patients, but they led to withdrawal of the antidepressant in only 2 cases, where dyspnea, palpitations, pollakiuria in a case and headache, nausea, dysuria in the other case occurred. The most frequent adverse event observed was hypotension (n = 6), but in each case it occurred just after the addition of sedative phenothiazines (n = 5) or of a comedication with phenothiazines and valpromide (n = 1). So this side-effect could not be attributed to milnacipran alone. Treatments with heptaminol or theodrenaline and cafedrine were useful. An increase of the cardiac frequency seemed to occur with milnacipran (p < 0.06). It was observed in the 5 inpatients for whom this cardiovascular parameter was recorded before and during the milnacipran treatment. In 5 other patients, the cardiac frequency seemed to decrease when milnacipran was stopped for lack of good efficacy or adverse events. Gastrointestinal disturbances were scarce isolated (nausea n = 1), but necessitated a treatment with metopimazine. The milnacipran prescription (100 mg/d) after an other antidepressant treatment had been done without a withdrawal period and without problem, even when the previous antidepressant was a SSRIs with a long half-life and CYP450 inhibitory properties. The authors concluded to the good tolerability of milnacipran in usual clinical practice.

[Grapefruit juice as a contraindication? An approach in psychiatry]. / Faut-il contre-indiquer le jus de pamplemousse? Une approche en psychiatrie.

The authors investigated in this preliminary study the influence of grapefruit juice on the metabolism of two tricyclic antidepressants. An increase of plasma concentrations is observed indeed for many drugs when administered concomitantly with grapefruit juice. This effect was mainly attributed to inhibition of cytochrome P450 1A2 and 3A4 enzymes by naringenin. These isoenzymes are involved too in the metabolism of many psychotropic drugs. Only two benzodiazepines (midazolam and triazolam) were studied in the conditions of grapefruit juice association. All these studies are performed in healthy subjects and with a study design very different from the clinical conditions. On the basis of these considerations, the authors hypothesized that grapefruit juice should inhibit tricyclic antidepressant metabolism and thus increase the bioavailability of these drugs. They want to precise if this possible drug plasma level increase could be clinically important for depressed patients. Fourteen depressed inpatients were selected for the study. Seven of them received amitriptyline (100 to 150 mg/d) and the seven others clomipramine (112.5 to 225 mg/d). Tricyclic antidepressant and desmethylated metabolite plasma levels were determined on four occasions. The first and second day samples were obtained to determined the plasma level intraindividual variability of antidepressants. On the third and fourth days, plasma levels were determined after an oral coadministration of the antidepressant and 250 ml of pure and fresh grapefruit juice. One patient was excluded from the study due to the coadministration of clomipramine and fluvoxamine. There is indeed a major drug-interaction between these two drugs, and the tricyclic antidepressant plasma levels of this patient were in the toxic range, without side effect. In this group of patients, there was no metabolic interaction between amitriptyline and grapefruit juice. But the mean plasma levels of clomipramine and desmethylclomipramine increased after coadministration of this juice (+4.5% and +10.5% respectively). The authors concluded that with these preliminary results, the potential clinical relevance of this interaction cannot be estimated.

Drug extrapyramidal side effects. CYP2D6 genotypes and phenotypes.

OBJECTIVE: Among Caucasians, a lack of cytochrome P450 enzyme CYP2D6 is observed in 5-10% of individuals, named poor metabolizers (PMs). A consequence may be an impaired metabolism of many drugs such as most of the psychotropic drugs with an increased risk of drug side effects. This enzyme is also involved in the metabolism of endogenous compounds, including neurotransmitters such as dopamine and dopamine-related neurotransmitters which play a role in the mechanism of action of extrapyramidal drug side effects. The present study investigates whether patients who have developed and those who have not developed extrapyramidal drug side effects differ in their CYP2D6 genotypes and phenotypes. METHODS: The CP2D6 genotype (method involving restriction length fragment polymorphism and polymerase chain reaction-single strand conformation polymorphism) was determined in 65 drug-treated in-patients, and the CYP2D6 phenotype (with dextromethorphan probe) in 62 of them. Two groups were constituted, one with 22 patients who had developed extrapyramidal drug side effects, and the second with 43 patients without such side effects. RESULTS: In the whole population, there was an over-representation of PM phenotypes--more marked in the first group than the second (45% vs 14%). Concerning the genotypes, we observed that the percentage of functional alleles (with extensive metabolic capacity) was higher in group 2, whereas the percentage of nonfunctional alleles (without metabolic activity) was higher in group 1; this frequency difference was only marginally significant (chi 2 5.95; P < 0.0509; degrees of freedom = 2). Consequently, there was a higher percentage of genotypes with no (extensive) functional alleles in the group of patients suffering from extrapyramidal side effects than in the other group (P < 0.00001). CONCLUSION: CYP2D6-impaired metabolic capacity may be a contributory factor in extrapyramidal drug side effects.

[Maprotiline versus fluvoxamine: comparison of their effects on the hypothalamo-hypophyseal-thyroid axis]. / Maprotiline versus fluvoxamine: comparaison entre leurs actions sur l'axe hypothalamo-hypophyso-thyroïdien.

The TRH test has been used in psychiatry these last 20 years. One of the most promising results is that concerning the possibility to use it to identify the best moment to stop a treatment after clinical recovery of the depressive episode. For that it is necessary to demonstrate an absence of intrinsic action of antidepressants on the HPT axis physiology. This overt, randomized study has compared the actions on T3, T4, basal TSH and its response to the TRH test after 75 mg/day of maprotiline and 100 mg/day of fluvoxamine, both administrated in depressed patients during 28 days. Forty patients (20 men and 20 women) were studied, 20 patients per treatment. The inclusion criteria were those of DSM III-R for major depression and dysthymia as well a minimum score of 25 at MADRS scale. Blood samples for T3, T4 and basal TSH dosages were made before TRH intranasal administration (2 mg) at days 1 and 28 of the treatment. We haven't observed any difference before treatment between the 2 groups for clinical and biological studied parameters. After treatment both antidepressants produced equivalent improvement of depression evaluated by MADRS (fluvoxamine:dMADRS = 16.95 +/- 7.11; maprotiline: dMADRS = 17.10 +/- 6.84. t = 0.07, NS). T3 and T4 variations between the beginning and the end of the study weren't also significantly different between the 2 groups. Basal TSH was increased in the maprotiline group but decreased in the fluvoxamine group resulting in a significant difference (fluvoxamine: dTSH = 0.31 +/- 0.76 mUI/l. Maprotiline : dTSH = -0.23 +/- 0.66 mUI/l. t = 2.40, p < 0.02). The TSH response to TRH was decreased in the fluvoxamine group (ddTSH = 0.24 +/- 6.65 mUI/l. dAUC = 103.98 +/- 596.84 mUI/l) while it was increased in the maprotiline group (ddTSH = -3.59 +/- 5.88 mUI/l. dAUC = -355.80 +/- 505.67 mUI.min/l). The difference between the 2 treatments was not significant when evaluated by ddTSH (t = 1.53, NS) but it became significant if evaluated by dAUC (t = 2.63, p < 0.01). As we could demonstrate an absence of influence of the clinical evolution between both groups in the hormonal variations observed, we concluded to a intrinsic difference action on HPT axis between fluvoxamine and maprotiline. This difference could be linked to the different aminergic action of these 2 antidepressants.