Remeron
Effectiveness of mirtazapine in the treatment of sleep apnea/hypopnea syndrome (SAHS).

Castillo JL, Menendez P, Segovia L, Guilleminault C.

Sleep Laboratory, Clinica Santa Maria, University of Chile, Santiago, Chile; Department of Neurology, University of Chile, Santiago, Chile.

Several drugs have been described as possible treatments for Sleep Apnea/Hypopnea Syndrome (SAHS) but the data available does not support their use. In an animal model of central apnea the use of mirtazapine produced a significant reduction of apneas. We present a male patient, 82 years old, with excessive daytime sleepiness and loud snoring during at least 10 years. An overnight polysomnography (PSG) revealed an apnea/hypopnea index of 54.9 events per hour of sleep with a minimum pulse oximetric saturation (SaO(2)) of 78% and an arousal index of 40.4 per hour. A nasal CPAP titration in the second half of the night showed suppression of apneas with a CPAP level of 8cmH(2)O. The patient refused to use the CPAP device and began with 15mg of mirtazapine at bedtime. A second PSG performed after 3 months of mirtazapine showed a significant reduction in the apnea/hypopnea index (9.3 events per hour of sleep; 81% minimal oxygen saturation (SaO(2))). Clinically, the patient and his wife reported a clear reduction of excessive daytime sleepiness and an improvement in self-reported functioning and well-being without any important side effects. This successful case appears to be the first report with mirtazapine in human SAHS and supports the need for an appropriate clinical trial with this drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15341898&dopt=Abstract mirtazapine Remeron



Remeron
Newer antidepressants in pregnancy: prospective outcome of a case series.

Yaris F, Kadioglu M, Kesim M, Ulku C, Yaris E, Kalyoncu NI, Unsal M.

Department of Family Medicine, School of Medicine, Karadeniz Technical University, TR-61187 Trabzon, Turkey. fyaris meds.ktu.edu.tr

Antidepressant drug choice in pregnancy is a complex problem especially for new drugs. Among 590 cases exposed to drugs during pregnancy who were followed by our center, 21 cases used newer antidepressants, i.e., venlafaxine, mirtazapine, nefazodone. We present the gestational findings and fetal outcomes of these cases. Ten cases had used venlafaxine, one case had used both venlafaxine and mirtazapine, eight had used mirtazapine alone or with some other drugs and two had used nefazodone, in the first trimester. Of the 21 cases, 17 (80.9%) had healthy babies, 3 (14.3%) decided to terminate the pregnancy, and 1 (4.8%) spontaneous abortion was observed in a case exposed to mirtazapine, alprazolam, diazepam and trifluoperazine. All obstetrical findings were normal during the pregnancy of each case. No congenital abnormality and developmental problem was observed in the babies followed up for 12 months. The aim of the present study is to contribute the data to the limited knowledge available in the literature regarding human pregnancy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15501389&dopt=Abstract mirtazapine Remeron



Remeron
The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression.

Szegedi A, Rujescu D, Tadic A, Muller MJ, Kohnen R, Stassen HH, Dahmen N.

Department of Psychiatry, Charite-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany. armin.szegedi charite.de

The catechol-O-methyltransferase (COMT) is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters such as dopamine and norepinephrine. This study investigated whether the functionally relevant Val(108/158)Met gene variant is associated with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized clinical trial with both drugs. In patients treated with mirtazapine, but not paroxetine, allelic variations in the COMT gene were associated with differential response. COMT(VAL/VAL) and COMT(VAL/MET) genotype carriers showed a better response than COMT(MET/MET)-bearing patients in the mirtazapine group. Moreover, carriers of the COMT(VAL/VAL) or COMT(VAL/MET) genotype had significantly greater HAMD-17 (Hamilton Rating Scale for Depression 17 item version) score reductions than COMT(MET/MET) homozygotes from week 2 to 6, respectively, in the mirtazapine group. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the COMT gene.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15520843&dopt=Abstract mirtazapine Remeron



Remeron
Enantioselective determination of the novel antidepressant mirtazapine and its active demethylated metabolite in human plasma by means of capillary electrophoresis.

Mandrioli R, Pucci V, Sabbioni C, Bartoletti C, Fanali S, Raggi MA.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

Mirtazapine is a recent noradrenergic and specific serotonergic antidepressant drug. A capillary electrophoretic method has been developed for the enantioseparation and analysis of mirtazapine and its main active metabolite, N-desmethylmirtazapine, in human plasma. For method optimisation several experimental parameters were investigated, such as type and concentration of the chiral selector, buffer pH and capillary temperature. Baseline enantioseparation of the analytes was achieved in 2.5 min in a fused silica capillary (50 microm i.d.; 48.5 cm total length; 8.5 cm effective length) using carboxymethyl-beta-cyclodextrin, dissolved in a background electrolyte consisting of 50 mM phosphate buffer at pH 2.5, as the chiral selector. UV detection was set at 205 nm. A careful pre-treatment of plasma samples was developed, using solid-phase extraction with hydrophilic-lipophilic balance cartridges (60 mg, 3 mL), eluting the sample with methanol, then concentrating it 37.5 times before injection. Extraction yield values are very satisfactory, being the average 89% for mirtazapine and 73% for N-desmethylmirtazapine. Application of the method to some human plasma samples has given satisfactory results.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15532581&dopt=Abstract mirtazapine Remeron



Remeron
Impact of the CYP2D6 ultrarapid metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volunteers.

Kirchheiner J, Henckel HB, Meineke I, Roots I, Brockmoller J.

Institute of Clinical Pharmacology, Humboldt University Berlin, Germany. Julia.kirchheiner charite.de

INTRODUCTION: In vitro studies showed that biotransformation of the antidepressant drug mirtazapine is mediated by cytochrome P-450 enzymes CYP1A2, CYP2D6, and CYP3A4 with CYP2D6 contributing about 35% to total mirtazapine biotransformation. We hypothesized that ultrarapid metabolizers (defined as carriers of the CYP2D6 gene duplication plus another functional allele) have a risk for therapeutic failure due to too low tissue concentrations. METHODS: Ten healthy male volunteers carrying 1 CYP2D6 duplication allele and 1 wild-type allele, 12 carriers of 2 CYP2D6 wild-type alleles and 3 carriers of 2 functionally inactive alleles received a single dose of 45 mg racemic mirtazapine and plasma concentrations were measured from 0 to 58 hours. RESULTS: Median total clearance of racemic mirtazapine (Cl/F) was 20.1, 39.7, and 49.8 L/h in carriers of 0, 2, and 3 active genes of CYP2D6 (P = 0.002, trend test) and the median maximum plasma concentrations were 129, 159, and 76 mug/L in these 3 groups. The effects on maximal blood concentrations may indicate a contribution of CYP2D6 on mirtazapine first-pass metabolism. A trend with lower concentrations in the high-activity CYP2D6 genotypes was also seen for the active metabolite desmethylmirtazapine, but without any significance. Mirtazapine concentrations showed a significant correlation with diastolic and systolic blood pressure (P = 0.05) and the correlation was even stronger when taking total mirtazapine (mirtazapine plus desmethylmirtazapine, P = 0.03), but neither blood pressure nor heart rate effects were correlated with CYP2D6 genotype. CONCLUSIONS: Consistent with the in vitro data, the genetically polymorphic enzyme CYP2D6 contributed to about 25% of total clearance in carriers of only one active allele and up to 55% in the genetically defined ultrarapid metabolizers. But the effect of the CYP2D6 gene duplication was lower than expected and high CYP2D6 activity may only explain a very small fraction of the cases with therapeutic failure in treatment with mirtazapine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15538128&dopt=Abstract mirtazapine Remeron



Remeron
CHRONIC DAILY HEADACHE AND MEDICATION-OVERUSE HEADACHE.

[No authors listed]

Bentsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology. 2004;62:1706-1711. Background: The tricyclic antidepressant amitriptyline is the only drug with prophylactic efficacy for chronic tension-type headache. However, amitriptyline is only moderately effective, with headache reduction of approximately 30%, and treatment is often hampered by side effects. Mirtazapine is a relatively new so-called noradrenergic and specific serotonergic antidepressant, which is more specific and therefore generally better tolerated. Objective: To evaluate the efficacy of mirtazapine. Methods: Twenty-four nondepressed patients with chronic tension-type headache were included in a randomized, double-blind, placebo-controlled, crossover trial. All patients had tried numerous other treatments. Mirtazapine 15 to 30 mg/day or placebo was each given for 8 weeks separated by a 2-week wash-out period. Results: Twenty-two patients completed the study. The primary efficacy variable, area-under-the-headache curve (AUC; duration x intensity), was lower during treatment with mirtazapine (843) than during treatment with placebo (1275) (P= .01). Mirtazapine also reduced the secondary efficacy variables headache frequency (P= .005), headache duration (P= .03), and headache intensity (P= .03) and was well tolerated. Conclusions: Mirtazapine reduced AUC by 34% more than placebo in difficult-to-treat patients. This finding is clinically relevant and may stimulate the development of prophylactic treatments with increased efficacy and fewer side effects for tension-type headache and other types of chronic pain. Comment: I am happy to see these results on mirtazepine for chronic tension-type headache (CTTH), and I look forward to prescribing it for daily headache, despite its occasional adverse events of weight gain and somnolence, similar to amitriptyline. It is probably not quite right to state, as the authors did, that "the tricyclic antidepressant amitriptyline is the only drug with prophylactic efficacy for CTTH." For example, here are two randomized controlled studies suggesting efficacy for two very different medications for CTTH: * Saper JR, Silberstein SD, Lake AE III, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache. 1994;34:497-502. * Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache. 2002;42:470-482.-Stewart J. Tepper Zwart J-A, Hagen K, Svebak S, Stovner LJ, Holmen J. Analgesic overuse among subjects with headache, neck, and low-back pain. Neurology. 2004;62:1540-1544. Objectives: To examine the prevalence of chronic headache (>/=15 days/month) associated with analgesic overuse in relation to age and gender and the association between analgesic overuse and chronic pain (ie, migraine, nonmigrainous headache, neck, and low-back pain). Methods: In the Nord-Trondelag Health Study 1995 to 1997 (HUNT-2), a total of 51 383 subjects responded to headache questions (Head-HUNT), of which 51 050 completed questions related to musculoskeletal symptoms and 49 064 questions regarding the use of analgesics. Results: The prevalence of chronic headache associated with analgesic use daily or almost daily for >/=1 month was 1% (1.3% for women and 0.7% for men) and for analgesic overuse duration of 3 months 0.9% (1.2% for women and 0.6% for men). Chronic headache was more than seven times more likely among those with analgesic overuse (>/=1 month) than those without (odds ratio [OR]= 7.5; 95%CI: 6.6 to 8.5). Upon analysis of the different chronic pain subgroups separately, the association with analgesic overuse was strongest for chronic migraine (OR = 10.3; 95%CI: 8.1 to 13.0), intermediate for chronic nonmigrainous headache (OR = 6.2; 95%CI: 5.3 to 7.2), and weakest for chronic neck (OR = 2.6, 95%CI: 2.3 to 2.9) and chronic low-back (OR = 3.0; 95%CI: 2.7 to 3.3) pain. The association became stronger with increasing duration of analgesic use for all groups and was most evident among those with headache, especially those with migraine. Conclusions: Chronic headache associated with analgesic overuse is prevalent and especially chronic migraine is more strongly associated with frequent intake of analgesics than other common pain conditions such as chronic neck and chronic low-back pain. Esposito SB, Gherpelli JL. Chronic daily headaches in children and adolescents: a study of clinical characteristics. Cephalalgia. 2004;24(6):476-482. The clinical characteristics of chronic daily headache were studied in 40 children and adolescents, as well as the associated factors responsible for maintenance of the continuous headache pattern. The study of the clinical headache characteristics, showed a female preponderance (75%), mean age of 11 years old at the first consultation, and onset of headache symptomatology at a mean age of 8.5 years old. The average time interval for the evolution of sporadic headache into chronic daily headache was 1.4 years, and psychosocial stressors were present, acutely or chronically, during the period of headache-frequency increase in 47% of the children. Headaches were classified as transformed migraine (65%), mixed pattern (17.5%), and chronic tension-type headache (17.5%). Sixty percent of patients had mothers with migraine. Data regarding common analgesic use showed an average intake of 11.2 days/month. Romero CE, Baron JD, Knox AP, Hinchey JA, Ropper AH. Barbiturate withdrawal following internet purchase of fioricet. Arch Neurol. 2004;61:1111-1112. Background: The Internet enables businesses to advertise their pharmaceutical products and services without medical supervision. The internet also allows for the unsupervised purchase of medications that may have neurologic consequences. Objective: To describe acute withdrawal delirium following the abrupt discontinuation of Fioricet. Patient: The patient was a 37-year-old woman with a history of depression and migraine headaches but not drug abuse. She developed a florid withdrawal delirium following the discontinuation of a drug she purchased online. The medication, which contained butalbital, was self-administered in escalating doses for the treatment of chronic headaches. Daily doses of up to 750 to 1000 mg were reported. Results: The patient was admitted to the hospital for the treatment of unexplained seizures that were followed by several days of an intense withdrawal syndrome. Little improvement was noted after the administration of benzodiazepines and phenothiazine. After parenteral phenobarbital administration, her symptoms resolved. Conclusions: The withdrawal state from barbiturates is similar to that from ethanol. Tolerance can develop with prolonged abuse, leading to escalating drug doses to achieve the desired effect. The suggested management of both types of withdrawal syndromes is similar, but the relative resistance of the behavioral and autonomic features in patients was remarkable. Physicians should be aware of the ease with which medications can be purchased without supervision from the Internet pharmacies. The magnitude of the number of drugs that are made available through this means creates a proclivity to withdrawal states. Comment: There are two take-home lessons here. The first lesson is that abrupt butalbital discontinuation can produce life-threatening barbiturate withdrawal. Drs. Elizabeth Loder and David Biondi wrote an indispensable guide to safe withdrawal of these patients in 2003 (Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43:904-909). The second lesson is that habituating, potentially life-threatening medications are available with ease on the internet, and we must be vigilant about asking our patients if they supplement our prescriptions. Dr. Steve Peroutka has written eloquently on headache information available on the internet (Peroutka S. Analysis of internet sites for headache. Cephalalgia. 2001;21:20-24). Romero et al's article describes sites for obtaining drugs.-Stewart J. Tepper Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Transformed migraine and medication overuse in a tertiary headache centre-clinical characteristics and treatment outcomes. Cephalalgia. 2004;24:483-490. Studies suggest that a substantial proportion of headache sufferers presenting to headache clinics may overuse acute medications. In some cases, overuse may be responsible for the development or maintenance of a chronic daily headache (CDH) syndrome. The objectives of this study are to evaluate patterns of analgesic overuse in patients consulting a headache centre and to compare the outcomes in a group of patients who discontinued medication overuse to those of a group who continued the overuse, in patients with similar age, sex, and psychological profile. We reviewed charts of 456 patients with transformed migraine (TM) and acute medication overuse defined by one of the following criteria: (1) simple analgesic use (>1000 mg ASA/acetaminophen) > 5 days/week; (2) combination analgesics use (caffeine and/or butalbital) > 3 tablets a day for > 3 days a week; (3) opiate use > 1 tablet a day for > 2 days a week; (4) ergotamine tartrate use: 1 mg PO or 0.5 mg PR for > 2 days a week. For triptans, we empirically considered overuse > 1 tablet per day for > 5 days per week. Patients who were able to undergo detoxification and did not overuse medication (based on the above definition) after 1 year of follow-up were considered to have successful detoxification (Group 1). Patients who were not able to discontinue offending agents, or returned to a pattern of medication overuse within 1 year were considered to have unsuccessful detoxification (Group 2). We compared the following outcomes after 1 year of follow-up: number of days with headache per month; intensity of headache; duration of headache; headache score (frequency x intensity). The majority of patients overused more than one type of medication. Numbers of tablets taken ranged from 1 to 30 each day (mean of 5.2). Forty-eight (10.5%) subjects took more than 10 tablets per day. Considering patients seen in the last 5 years, we found the following overused substances: butalbital containing combination products, 48%; acetaminophen, 46.2%; opioids, 33.3%; ASA, 32.0%; ergotamine tartrate, 11.8%; sumatriptan, 10.7%; nonsteroidal anti-inflammatory medications other than ASA, 9.8%; zolmitriptan, 4.6%; rizatriptan, 1.9%; naratriptan, 0.6%. Total of all triptans, 17.8%. Of 456 patients, 318 (69.7%) were successfully detoxified (Group 1) and 138 (30.3%) were not (Group 2). The comparison between groups 1 and 2 after 1 year of follow-up showed a decrease in the frequency of headache of 73.7% in group 1 and only 17.2% in group 2 (P < .0001). Similarly, the duration of head pain was reduced by 61.2% in group 1 and 14.8% in group 2 (P < .0001). The headache score after 1 year was 18.8 in group 1 and 54 in group 2 (P < .0001). A total of 225 (70.7%) successfully detoxified subjects in Group 1 returned to an episodic pattern of migraine, compared to 21 (15.3%) in Group 2 (P < .001). More rigorous prescribing guidelines for patients with frequent headaches are urgently needed. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications. Comment: This study highlights the difficulties faced in trying to obtain outpatient provision for successful detoxification. Isn't it about time the FDA took a fresh look at the risk/benefits for butobarbital combinations, which are still surprisingly available in the United States? Surely this must signal the death knell for these products. The New England Center for Headache have a tremendous database of knowledge on which to base pragmatic prescribing guidelines. I would endorse their concern and commend the approach they have taken.-David S. Millson Torbey MT, Geocadin RG, Razumovsky AY, Rigamonti D, Williams MA. Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache. Cephalalgia. 2004;24:495-502. The aim of the present study was to report on the utility of continuous Pcsf monitoring in establishing the diagnosis of idiopathic intracranial hypertension without papilledema (IIHWOP) in chronic daily headache (CDH) patients. We report a series of patients (n = 10) with refractory headaches and suspected IIHWOP referred to us for continuous Pcsf monitoring between 1991 and 2000. Pcsf was measured via a lumbar catheter and analyzed for mean, peak, highest pulse amplitude, and abnormal waveforms. A 1 to 2 day trial of continuous controlled CSF drainage (10 cc/hour) followed Pcsf monitoring. Response to CSF drainage was defined as improvement in headache symptoms. Patients with abnormal waveforms underwent a ventriculoperitoneal (VPS) or lumboperitoneal (LPS) shunt insertion. All patients had normal resting Pcsf (8 +/- 1 mmHg) defined as ICP < 15 mmHg. During sleep, all patients had B-waves and 90% had plateau waves or near plateau waves. All patients underwent either a VPS or LPS procedure. All reported improvement of their headache after surgery. Demonstration of pathological Pcsf patterns by continuous Pcsf monitoring was essential in confirming the diagnosis of IIHWOP, and provided objective evidence to support the decision for shunt surgery. Increased Pcsf was seen mostly during sleep and was intermittent, suggesting that Pcsf elevation may be missed by a single spot-check LP measurement. The similarity between IIHWOP and CDH suggests that continuous Pcsf monitoring in CDH patients may have an important diagnostic role that should be further investigated. Comment: This study confirms that elevated CSF pressure, as measured by continuous CSF pressure monitoring, may be linked to CDH.-Stewart J. Tepper.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15546281&dopt=Abstract mirtazapine Remeron