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Topamax (Topiramate-Generic)
Zarontin (Ethosuximide-Generic
Anticonvulsants and Birth DefectsEpilepsia 2002 Aug;43(8):929-31
:
Is there an association between maternal carbamazepine use
during pregnancy and eye malformations in the child?
Kroes HY, Reefhuis J, Cornel MC
.
Department of Medical Genetics,
University Medical Center Utrecht,
Utrecht, The Netherlands.
PURPOSE: To check for an association between carbamazepine (CBZ) use by
the mother during pregnancy and congenital eye malformations (i.e.,
anophthalmia, microphthalmia, and coloboma) in the child, as suggested by
Sutcliffe et al. (1998), who reported four cases. METHODS: We checked all
the cases with these eye malformations for CBZ use by the mother in the
EUROCAT Northern Netherlands dataset, which registers infants with
congenital malformations and records possible teratogenic exposures
(including medication taken by the mother). We also reviewed 13 studies in the
literature. RESULTS: The EUROCAT dataset recorded 77 cases of
anophthalmia, microphthalmia, or coloboma, but none with prenatal exposure to
CBZ. Prenatal CBZ exposure was recorded in seven other cases without
congenital eye malformation. Large studies in the literature on the teratogenic
effects of CBZ (and other antiepileptic drugs), including data from the
MADRE database, revealed no association between these congenital eye
malformations and prenatal CBZ exposure. One case reported bilateral
anophthalmia and other congenital anomalies after prenatal exposure to CBZ
in combination with vigabatrin and dexamethasone. CONCLUSIONS: Our data
do not support Sutcliffe's suggestion that prenatal CBZ exposure may result
in congenital eye malformations. However, despite the large population
represented, both the low birth prevalence of these congenital eye
malformations and the low prevalence of CBZ exposure during pregnancy make
it difficult to exclude an increased relative risk. The many large prospective
and retrospective studies in the literature seem to agree with our findings,
although there is still uncertainty about the teratogenic effect of CBZ in
polytherapy.
Ann Pharmacother 2002 Apr;36(4):644-7
:
Neonatal cholestatic hepatitis from carbamazepine exposure
during pregnancy and breast feeding.:
Frey B, Braegger CP, Ghelfi D.
Department of Intensive Care and Neonatology,
University Children's
Hospital, Zurich, Switzerland.
Bernhard.Frey@kispi.unizh.ch
OBJECTIVE: To report a case of transient cholestatic hepatitis occurring in
an infant between the third and seventh weeks of life, most likely due to
carbamazepine exposure during pregnancy and breast feeding. CASE
SUMMARY: A boy, born to an epileptic mother who had been treated with
carbamazepine monotherapy throughout pregnancy and breast feeding,
experienced asphyxia at birth with transient hepatic dysfunction in the first
week of life. After full recovery from asphyxia, he experienced a second
period of liver dysfunction, presenting as cholestatic hepatitis that lasted
approximately 5 weeks. Infectious and metabolic etiologies as well as
extrahepatic biliary atresia were excluded. DISCUSSION: Carbamazepine is
known to induce hepatic damage in children and adults. As the drug crosses the
placenta and is excreted into breast milk, infants of mothers taking
carbamazepine might also develop liver dysfunction. In addition to the
present case, there are 2 well-documented case reports of cholestasis in
association with transplacental and transmammary carbamazepine exposure.
CONCLUSIONS: Carbamazepine-induced hepatitis may occur in association
with prenatal exposure and breast feeding. This may expose infants to
unnecessary diagnostic procedures, and should therefore be mentioned in the
company's product information.
J Affect Disord 2002 Dec;72 Suppl:S23-34 :
Oxcarbazepine (Trileptal) in the treatment of bipolar disorders: a review of efficacy and tolerability.
Hellewell JS.
Department of Psychiatry, Trafford General Hospital, Moorside Road, Urmston, M41 5SL, Manchester, UK
Oxcarbazepine, although structurally similar to carbamazepine, is metabolised very differently. As a consequence, oxcarbazepine's pharmacokinetic profile is comparatively less complex, and a more predictable, linear relationship between oxcarbazepine and blood levels is apparent. Furthermore, hepatic enzyme induction is considerably less with oxcarbazepine. Unlike carbamazepine, oxcarbazepine does not appear to induce its own metabolism, nor is it highly protein bound. These pharmacokinetic and metabolic characteristics raise the expectation that potential for drug interactions and side effects with oxycarbazepine will be less than that reported for carbamazepine. This review compares the pharmacokinetic and metabolic profiles of the two drugs and the available efficacy and safety data of carbamazepine and oxcarbazepine, in the treatment of bipolar disorder.
: J Pain Symptom Manage 2003 May;25(5 Suppl):S31-5 :
Rationale and evidence for the use of oxcarbazepine in neuropathic pain.
Carrazana E, Mikoshiba I.
Neuroscience, Clinical Development and Medical Affairs, Novartis Pharmaceuticals, East Hanover, NJ, USA
Oxcarbazepine is a second-generation antiepileptic drug (AED) with proven efficacy in managing partial epileptic seizures, with or without secondary generalization, in adults and children. The overlap between the underlying pathophysiologic mechanisms of some epilepsy models and neuropathic pain models supports the rationale for using certain AEDs in the treatment of neuropathic pain. Several AEDs have reportedly produced analgesia in a range of neuropathic pains, including painful diabetic neuropathy (PDN) and post-herpetic neuralgia. Increasing evidence suggests that oxcarbazepine can provide significant analgesia in several neuropathic pain conditions, including trigeminal neuralgia and PDN, and is also may be effective in treating neuropathic pain refractory to other AEDs, such as carbamazepine and gabapentin. The analgesic effects of oxcarbazepine, and its generally improved safety and tolerability profile compared with other standard AEDs, suggests that oxcarbazepine will be an important addition to the neuropathic pain armamentarium. The rationale and evidence to support the efficacy of oxcarbazepine are presented here.
Reprod Toxicol 2002 Jan-Feb;16(1):9-17
:
The teratogenic effect of carbamazepine: a meta-analysis of
1255 exposures.
Matalon S, Schechtman S, Goldzweig G, Ornoy A.
Laboratory of Teratology, Department of Anatomy & Cell Biology,
Hebrew
University Hadassah Medical School, Jerusalem, Israel.
Maternal use of antiepileptic drugs during pregnancy has been associated with
an increased risk of major congenital abnormalities in the fetus.
Carbamazepine (CBZ) is an antiepileptic drug that was developed and
marketed mainly for the treatment of epileptic seizures. Some investigators
described an increased rate of major congenital anomalies following treatment
with CBZ during pregnancy while others found no such increase. In order to
quantify better the risks of exposure to CBZ during pregnancy, we pooled
data from prospective studies known to us. We found in prospective studies
involving 1255 cases of exposure that CBZ therapy increased the rate of
congenital anomalies, mainly neural tube defects, cardiovascular and urinary
tract anomalies, and cleft palate. CBZ may also induce a pattern of minor
congenital anomalies and developmental retardation, but our study did not
address these endpoints. CBZ also appears to reduce gestational age at
delivery. A combination of CBZ with other antiepileptic drugs is more
teratogenic than CBZ monotherapy. Children born to untreated epileptic
women do not appear to have an increased rate of major birth defects. In
light of these results, we recommend performing a level 2 ultrasound and fetal
echocardiography in women treated with CBZ during pregnancy.
Neurology 2001 Jul 24;57(2):321-4
:
Is carbamazepine teratogenic? A prospective controlled study of
210 pregnancies.
Diav-Citrin O, Shechtman S, Arnon J, Ornoy A.
Israeli Teratogen Information Service,
Laboratory of Teratology, Jerusalem,
Israel.
The Israeli Teratogen Information Service prospectively followed up 210
pregnancies with first trimester carbamazepine exposure. Pregnancy outcome
was compared with that of two overlapping controls, matched and general (n =
629), exposed to nonteratogenic agents. Our study suggests a twofold
increase in the rate of major congenital anomalies (12/160 [carbamazepine]
versus 18/560 [general control]; relative risk 2.24; 95% CI 1.1-4.56) and a
birth weight reduction of approximately 250 g after in utero exposure to
carbamazepine.
Ann Neurol 1999 Nov;46(5):739-46
:
Antiepileptic drug regimens and major congenital abnormalities in
the offspring.
Samren EB, van Duijn CM, Christiaens GC, Hofman A, Lindhout D.
Department of Clinical Genetics,
University Hospital Rotterdam/Dijkzigt,
The Netherlands.
To assess the risk of major congenital abnormalities associated with specific
antiepileptic drug regimens, a large retrospective cohort study was
performed. The study comprised 1,411 children born between 1972 and 1992
in four provinces in The Netherlands who were born to mothers with epilepsy
and using antiepileptic drugs during the first trimester of pregnancy, and
2,000 nonepileptic matched controls. We found significantly increased risks
of major congenital abnormalities for carbamazepine and valproate
monotherapy, with evidence for a significant dose-response relationship for
valproate. The risk of major congenital abnormalities was nonsignificantly
increased for phenobarbital monotherapy when caffeine comedication was
excluded, but a significant increase in risk was found when caffeine was
included. Phenytoin monotherapy was not associated with an increased risk of
major congenital abnormalities. Regarding polytherapy regimens, increased
risks were found for several antiepileptic drug combinations. Clonazepam, in
combination with other antiepileptic drugs, showed a significantly increased
relative risk. Furthermore, there were significantly increased relative risks
for the combination of carbamazepine and valproate and the combination of
phenobarbital and caffeine with other antiepileptic drugs. This study shows
that most antiepileptic drug regimens were associated with an increased risk
of major congenital abnormalities in the offspring, in particular valproate
(dose-response relationship) and carbamazepine monotherapy,
benzodiazepines in polytherapy, and caffeine comedication in combinations
with phenobarbital.
Epilepsia 1999 Sep;40(9):1231-6
:
Malformations in offspring of women with epilepsy: a prospective
study.
Canger R, Battino D, Canevini MP, Fumarola C, Guidolin L, Vignoli A, Mamoli
D, Palmieri C, Molteni F, Granata T, Hassibi P, Zamperini P, Pardi G,
Avanzini G.
Regional Epilepsy Center, University of Milan Medical School,
San Paolo
Hospital, Italy.
crehsp@imiucca.csi.unimi.it
PURPOSE: The incidence of malformations among infants of mothers with
epilepsy treated with antiepileptic drugs (AEDs) during pregnancy is higher
than that found in the general population. The aim of this study was to
contribute to providing a definition of the rate of congenital anomalies in the
offspring of mothers with epilepsy and to detect possible risk factors.
METHODS: Since 1977, 517 pregnancies were followed up at the San Paolo
Hospital in Milan by a team of epileptologists and obstetricians. The patients
received monthly obstetric and neurologic examinations, and the blood levels
of AEDs were tested monthly. During pregnancy the patients underwent
ultrasound investigations to evaluate fetal morphology and development. At
the time of delivery, the infants were submitted to a standardized
examination by a pediatrician, and a more detailed clinical examination was
performed on day 5. Malformations were classified as (a) genetic and
chromosomic, (b) severe and mild malformations, and (c) deformities.
RESULTS: The overall rate of malformations was 9.7%: of these, 5.3% were
structurally severe, 2.2% were mild, 0.4% were chromosomic-genetic, and
1.8% were deformities. No malformation was detected in the 25 untreated
patients. CONCLUSIONS: The risks of teratogenicity have been regarded as
multifactorial, involving such factors as genetic predisposition, although most
prospective studies show that AED-related factors are the primary risk
factors for an increased incidence of congenital malformations.
: Epilepsy Res 1999 Feb;33(2-3):145-58
:
Congenital malformations due to antiepileptic drugs.
Kaneko S, Battino D, Andermann E, Wada K, Kan R, Takeda A, Nakane Y,
Ogawa Y, Avanzini G, Fumarola C, Granata T, Molteni F, Pardi G, Minotti L,
Canger R, Dansky L, Oguni M, Lopes-Cendas I, Sherwin A, Andermann F,
Seni MH, Okada M, Teranishi T.
Department of Neuropsychiatry,
Hirosaki University, Japan.
To identify the major risk factors for the increased incidence of congenital
malformations in offspring of mothers being treated for epilepsy with
antiepileptic drugs (AEDs) during pregnancy and, to determine the relative
teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in
Japan, Italy, and Canada. The incidence of congenital malformations in
offspring without drug exposure was 3.1%, versus an incidence with drug
exposure of 9.0%. The highest incidence in offspring exposed to a single AED
occurred with primidone (PRM; 14.3%), which was followed by valproate
(VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and
phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with
the incidence of malformations. This study first determined a cut-off value of
VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid
the occurrence of malformations. The incidence of malformations increases as
the number of drugs increases, and as the total daily dose increases. Specific
combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a
higher incidence of congenital malformations. The incidence of malformations
was not associated with any background factors studied except for the
presence of malformations in siblings. These results indicate that the
increased incidence of congenital malformations was caused primarily by
AEDs, suggesting that malformations can be prevented by improvements in
drug regimen, and by avoiding polypharmacy and high levels of VPA (more than
70 microg/ml) in the treatment of epileptic women of childbearimg Anticonvulsants and Use with Neuropathic Painage.
Clin Infect Dis 2003 Apr 1;36(7):877-82 :
Treatment and prevention of postherpetic neuralgia.
Dworkin RH, Schmader KE.
Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
robert_dworkin@urmc.rochester.edu
There have been 4 recent major advances in the treatment of postherpetic neuralgia (PHN) that are based on the results of randomized, controlled trials. These advances are the demonstrations that gabapentin, the lidocaine patch 5%, and opioid analgesics are efficacious in patients with PHN, and the report that nortriptyline and amitriptyline provide equivalent analgesic benefits for patients with PHN but that nortriptyline is better tolerated. The results of these clinical trials are briefly reviewed, and their implications for the treatment of patients with PHN are discussed. Despite these treatment advances, many patients remain refractory to current therapy, and the prevention of PHN has therefore become an important focus of current research. Research on administration of the varicella-zoster vaccine to prevent herpes zoster and on treatment of patients who have herpes zoster with combined antiviral and analgesic therapy to prevent PHN is discussed.
Clin Ther 2003 Jan;25(1):81-104 :
Gabapentin dosing for neuropathic pain: Evidence from randomized, placebo-controlled clinical trials.
Backonja M, Glanzman RL.
Department of Neurology, Anesthesiology, and Rehabilitation Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
BACKGROUND: Pain is one of the most common reasons for seeking medical attention, and neuropathic pain is among the most common types of pain. Despite its prevalence, neuropathic pain is often underrecognized and inadequately treated. Many cases are refractory to the medications traditionally used for pain, such as nonsteroidal anti-inflammatory drugs. Tricyclic antidepressants are considered first-line agents for neuropathic pain, but their use is limited by unwanted side effects and a risk of cardiovascular mortality.OBJECTIVES: The goals of this article were to review data on the efficacy and tolerability of gabapentin in the treatment of neuropathic pain in adults and to determine the optimal dosing schedule.METHODS: Randomized controlled studies of gabapentin for neuropathic pain were identified through a search of PubMed and MEDLINE from 1966 to the present using the search terms gabapentin, randomized, placebo, and pain. Abstracts of identified articles were screened for study size (>100 patients per treatment arm) and use of appropriate efficacy measures. A separate review based on information provided by the manufacturer of gabapentinaand clinical trial Web sites was conducted to ascertain whether there had been any other relevant industry- or government-sponsored trials. The manufacturer provided additional unpublshed study data.RESULTS: Data from 5 randomized, placebo-controlled trials were included in the review, 1 of which has not yet been published. Gabapentin was effective in the treatment of painful diabetic neuropathy, postherpetic neuralgia, and other neuropathic pain syndromes. It relieved symptoms of allodynia, burning pain, shooting pain, and hyperesthesia. Adverse effects were typically mild to moderate and usually subsided within approximately 10 days from the initiation of treatment. Based on available data, it appears that treatment should be started at a dose of 900 mg/d (300 mg/d on day 1, 600 mg/d on day 2, and 900 mg/d on day 3). Additional titration to 1800 mg/d is recommended for greater efficacy. Doses up to 3600 mg/d may be needed in some patients. The effective dose should be individualized according to patient response and tolerability.CONCLUSION: At doses of 1800 to 3600 mg/d, gabapentin was effective and well tolerated in the treatment of adults with neuropathic pain.
Rev Neurol 2002 Dec 1-15;35(11):1037-48 :
[Advances in physiopathology and the treatment of neuropathic pain]
[Article in Spanish]
Caviedes BE, Herranz JL.
Servicio de Neuropediatria. Hospital Marques de Valdecilla. Universidad de Cantabria, Santander, Espana.
pedhfj@humv.es
AIMS: In this paper we review the most significant studies on the treatment of neuropathic pain over the last few decades, as well as the most recent research work in which the physiopathological mechanisms of pain, with the intention of looking for evidence based criteria that can help us to choose the most appropriate treatment. METHOD: The physiopathological bases of neuropathic pain are founded, peripherally, on alterations in the neuronal excitability mediated by voltage dependent sodium channels; from the central point of view, the chief neurotransmitter involved is glutamate, which allows calcium to enter through the N-methyl D-aspartate receptor and conditions a more prolonged depolarisation and the activation of secondary messengers. This determines the chronification of the pain. Thanks to these physiopathological findings about pain, some of the new antiepileptics, which inhibit the sodium channels or the calcium channels, increase the GABA or reduce the level of glutamate in the synapses, have been added to the already existing classic forms of medication. CONCLUSIONS: Different neurophysical alterations induce the most diverse clinical manifestations, such as paresthesia, hyperalgesia or allodynia, regardless of the etiological processes that condition them. The efficiency of tricyclic antidepressants and of carbamazepine is made clear in different clinical studies, but the new antiepileptics (with the exception of gabapentin) have frequently been used in open clinical studies, which means there is a need for double blind controlled clinical trials in order to determine the efficiency and the tolerability of the different therapeutic alternatives in each of the clinical manifestations of neuropathic pain.
Neurology 2002 Sep 10;59(5 Suppl 2):S14-7:
Use of anticonvulsants for treatment of neuropathic pain.
Backonja MM.
Department of Neurology, University of Wisconsin Hospital and Clinics, Room H6/574, 600 Highland Avenue, Madison, WI 53792-5132, USA.
backonja@neurology.wisc.edu
Emerging evidence from animal models of neuropathic pain suggests that many pathophysiologic and biochemical changes occur in the peripheral and central nervous system. Similarities between the pathophysiologic phenomena observed in some epilepsy models and in neuropathic pain models justify the use of anticonvulsants in the symptomatic management of neuropathic pain. Positive results from laboratory and clinical trials further support such use. Carbamazepine was the first of this class of drugs to be studied in clinical trials and has been longest in use for treatment of neuropathic pain. Clinical trial data support its use in treating trigeminal neuralgia, but data for treatment of painful diabetic neuropathy are less convincing. Use of newer anticonvulsants has marked a new era in the treatment of neuropathic pain. Gabapentin has demonstrated efficacy, specifically in painful diabetic neuropathy and postherpetic neuralgia. Lamotrigine has been reported to be effective in relieving pain from trigeminal neuralgia refractory to other treatments, HIV neuropathy, and central post-stroke pain. Results from clinical trials of phenytoin are equivocal. Zonisamide's mechanisms of action suggest that it would be effective in controlling neuropathic pain symptoms. Other anticonvulsants, including lorazepam, valproate, topiramate, and tiagabine, have also been under investigation. Anecdotal experience provides support for studies with oxcarbazepine and levetiracetam for treating neuropathic pain. Evidence supporting the efficacy of anticonvulsants in treatment of such pain is evolving. Additional clinical trials should provide information that will better define their role in neuropathic pain.
Spine 2003 Feb 15;28(4):341-6; discussion 346-7 :
Gabapentin effect on neuropathic pain compared among patients with spinal cord injury and different durations of symptoms.
Ahn SH, Park HW, Lee BS, Moon HW, Jang SH, Sakong J, Bae JH.
Department of Rehabilitation Medicine, College of Medicine, Yeungnam University, Daegu, Korea.
STUDY DESIGN: This study evaluated the effect of gabapentin on neuropathic pain in patients with spinal cord injury. OBJECTIVE: To compare the effect of gabapentin on neuropathic pain refractory to conventional analgesics in patients with spinal cord injury and different durations of symptoms. SUMMARY OF BACKGROUND DATA: Neuropathic pain in patients with spinal cord injury severely compromises their quality of life. Gabapentin is a new antiepileptic drug that may additionally have a role in the treatment of neuropathic pain. So far, there has been little prospective research investigating the effect of gabapentin on neuropathic pain in patients after spinal cord injury or comparing gabapentin-treated patients with varying durations of symptoms after spinal cord injury. METHODS: The study included 31 patients who had experienced neuropathic pain associated with spinal cord injury or cauda equina syndrome. These subjects were divided into two groups. Group 1 (n = 13) was composed of patients whose duration of pain was less than 6 months, and Group 2 (n = 18) comprised patients whose symptoms of neuropathic pain had lasted more than 6 months. Although these patients had been treated with conventional analgesics such as antidepressants, anticonvulsants, membrane stabilizer, and neuroleptics, they reported that their condition did not improve after a medication trial of at least 2 weeks duration. In this study, conventional analgesics were continued at a therapeutic level, and gabapentin was administrated for an 18-day titration period followed by a 5-week maintenance period at a dosage of 1800 mg/day or the maximum tolerable dosage. The efficacy of gabapentin administration was gauged by a pain score and a sleep interference score using a 100-mm visual analogue scale (VAS) every 2 weeks. The scores of the two groups were compared every 2 weeks over the course of the 8-week study. RESULTS: The mean pain score and the mean sleep interference score for Group 1 decreased more than that of Group 2 during the interval between 2 to 8 weeks (P < 0.05). The mean pain score for Group 1 decreased from 7.3 +/- 0.5 initially to 3 +/- 0.6 after 8 weeks of treatment, whereas the corresponding score for Group 2 decreased from 7.6 +/- 0.4 to 5.1 +/- 0.6 ( < 0.05). The mean sleep interference score for Group 1 decreased from 5.7 +/- 0.9 initially to 1.8 +/- 0.8 after 8 weeks of treatment, whereas the corresponding score for Group 2 decreased from 5.9 +/- 0.8 to 4.2 +/- 0.7 (P < 0.05). As compared with the onset of this study, a decrease in pain score of 2 or more was reported at the completion of this study for 11 patients (100%) in Group 1 and 10 (71%) of 14 patients in Group 2. A decrease of 2 or more in sleep interference scores was reported for 8 (89%) of 9 patients with sleep interference in Group 1 and for 8 (62%) of 13 patients with sleep interference in Group 2. Some adverse effects such as somnolence were noted, but they were mild or moderate in intensity. CONCLUSIONS: Gabapentin may be effective in decreasing neuropathic pain refractory to conventional analgesics in some patients with spinal cord injury whose duration of symptoms is less than 6 months, although those with duration of symptoms longer than 6 months showed a significant decrease as well. The drug is unlikely to cause serious adverse effects that limit its use in patients with spinal cord injury.
Curr Pain Headache Rep 2003 Feb;7(1):24-33 :
Antidepressants for chronic neuropathic pain.
Reisner L.
University of California, San Francisco, Department of Clinical Pharmacy, Box 0622, San Francisco, CA 94143, USA.
reisnerL@pamf.org
Tricyclic antidepressants have been used to manage pain for several decades, and are superior treatments for some patients suffering from neuropathic pain. Unfortunately, older antidepressants have dose-limiting side effects that can lead to drug intolerance. The most common are anticholinergic side effects, although some patients experience sexual dysfunction. Cognitive impairment, sedation, and orthostatic hypotension also are relatively common. Taking an overdose of tricyclic antidepressants can be lethal in overdose. Several weeks of therapy may be required before antinociception occurs, but tricyclic antidepressants in optimal doses appear to be the most effective treatment for neuropathic pain; this is supported by systematic reviews comparing them with other agents. Newer medications such as atypical antidepressants and anticonvulsants may be overtaking older antidepressants, but they should not be overlooked as important options for the management of pain.
ANTICONVULSANTS AND BIPOLAR DISORDER
Actas Esp Psiquiatr 2003 May;31(3):149-155:
[Up-date in the treatment of rapid cycling and other refractory bipolar disorders]
[Article in Spanish]
Fernandez I, De Frutos M, Lujan E, Ortiz Del Romero J.
Introduction: Up-date in the treatment of rapid cycling and other resistant bipolar disorders. Methods: A Medline research of the literature was performed in several databases as Pub-Med, Cochrane and Embasse, from 1998 to December 2001. We have also reviewed bibliography supplied by different laboratories and several monographies. Results: 30 articles were selected: 11 reviews, 17 openlabeled studies and 2 articles on general recommendations. From the 17 open-labaled studies, 10 were on topiramate (25 to 400 mg/day) as a coadjuvant of another stabilizer. Improvement ranged from 40 to 70%; 4 adding gabapentin to the previous treatment, at the dosage of 60 to 5,600 mg/day, 27 and 92% showed improvement; 1 with mexiletine (200 to 1,200 mg/day) in which 46% were full responders, 15% partial responders and 38 % had no response, 100% response in manic or mixed and 38 % in depressed patients; and 2 with lamotrigine (50 to 500 mg/day) in which 52 to 80 % showed improvement. With risperidone at the dosage of 2-3 mg/day as coadjuvant, improvement was seen in 62 %. Olanzapine had direct short-term antimanic effects, with 49 % improvement in single drug therapy and 57 % as coadjuvant. Conclusions: More double-blind studies are necessary to assess efficacy in monotherapy or as coadjuvants, in short-term or even in monotherapy, and to compare the different treatments with each other as well as with the conventional treatment. The authors agree in pointing out the efficacy of gabapentin and topiramate associated to another stabilizer, and also of lamotrigine in depressed phases. Actas Esp Psiquiatr 2003;31(3):149-155
oxcarbazepine-Trileptal
: Bipolar Disord 2002 Dec;4(6):412-7:
Acute antimanic efficacy and safety of oxcarbazepine in an open trial with an on-off-on design.
Hummel B, Walden J, Stampfer R, Dittmann S, Amann B, Sterr A, Schaefer M, Frye MA, Grunze H.
Stanley Foundation Bipolar Network Centers, Department of Psychiatry, LMU Munich, Germany.
robert.stampfer@psy.med.uni-muenchen.de
RATIONALE AND OBJECTIVES: Carbamazepine has shown reasonable antimanic properties, but its use has been limited because of enzyme-inducing effects. The keto-derivative oxcarbazepine (OXC) is very similar to carbamazepine, however, the metabolic pathway is different. OXC is not metabolized to the 10, 11-epoxide, which seems to be responsible for several undesirable side-effects of carbamazepine and furthermore OXC has less enzyme-inducing properties. METHODS: In this non-random open label study, patients were treated with OXC for 14 days, crossed over to no OXC for 7 days, and then crossed back over to OXC for the remaining 14 days. OXC was titrated to a final dose in a range of 900-2100 mg due to individual response. Treatment success was defined as a reduction of the original Young Mania Rating Scale (YMRS) score of more than 50% at the end of study period. RESULTS: Four of the 12 included patients (33%) met defined response criteria at the end of study period. Fifty percentage of the patients had to be prematurely excluded from the trial. The mean YMRS scores of the on-periods were obviously different from the off-period. Forty-two percentage of the patients experienced side-effects leading to premature discontinuation in two of 12 patients. CONCLUSION: Antimanic activity of OXC was demonstrated in this pilot study only for patients with mild or moderate manic symptoms. Further studies are encouraged to clarify OXC's role as mood-stabilizer and assess whether it has a profile similar to that of carbamazepine.
J Affect Disord 2002 Dec;72 Suppl:S23-34 :
Oxcarbazepine (Trileptal) in the treatment of bipolar disorders: a review of efficacy and tolerability.
Hellewell JS.
Department of Psychiatry, Trafford General Hospital, Moorside Road, Urmston, M41 5SL, Manchester, UK
Oxcarbazepine, although structurally similar to carbamazepine, is metabolised very differently. As a consequence, oxcarbazepine's pharmacokinetic profile is comparatively less complex, and a more predictable, linear relationship between oxcarbazepine and blood levels is apparent. Furthermore, hepatic enzyme induction is considerably less with oxcarbazepine. Unlike carbamazepine, oxcarbazepine does not appear to induce its own metabolism, nor is it highly protein bound. These pharmacokinetic and metabolic characteristics raise the expectation that potential for drug interactions and side effects with oxycarbazepine will be less than that reported for carbamazepine. This review compares the pharmacokinetic and metabolic profiles of the two drugs and the available efficacy and safety data of carbamazepine and oxcarbazepine, in the treatment of bipolar disorder
J Affect Disord 2002 Dec;72 Suppl:S15-21 :
Relevance of new and newly rediscovered anticonvulsants for atypical forms of bipolar disorder.
Grunze H, Walden J.
Department of Psychiatry, LMU, Nussbaumstr. 7, D-80336, Munich, Germany
The so-called atypical forms of bipolar disorder are not a rarity, but instead are rather the rule. Particularly in specialized settings such as the bipolar disorder clinic, the majority of patients are characterized by atypical manifestations (). Mixed states, psychotic mania and a rapid cycling course of bipolar disorder are a challenge both to pharmacological and non-pharmacological treatment. The benefit of classical mood stabilizers such as lithium and carbamazepine is limited in monotherapy, although valproate has a broader spectrum of activity in atypical bipolar disorders and is often used in combination with other agents. Thus, new treatment alternatives are needed urgently for optimizing the treatment of atypical bipolar disorder. During the last decade, several new antiepileptic drugs have been released, e.g. lamotrigine, gabapentin, tiagabine, topiramate and levetiracetam. Others have been available for some time, but only recently have become the focus of bipolar disorder research; for example, phenytoin, and especially, oxcarbazepine. This review will consider our current knowledge of the benefit of these new and newly rediscovered anticonvulsants in treating bipolar disorders, with a special focus on their value in treating atypical manifestations.
Bipolar Disord 2002 Feb;4(1):70-4 :
Oxcarbazepine treatment of refractory bipolar disorder: a retrospective chart review.
Nassir Ghaemi S, Ko JY, Katzow JJ.
Bipolar Disorder Research Program, Cambridge Hospital, Cambridge, MA 02139, USA.
ghaemi@hms.harvard.edu
OBJECTIVE: To determine if oxcarbazepine is effective as treatment for refractory bipolar illness in a naturalistic setting. METHODS: All charts of out-patients treated with oxcarbazepine (n=13) were reviewed and clinical response assessed retrospectively using the Clinical Global Impression of Improvement (CGI-I) rating scale. All patients had failed treatment with at least one previous mood stabilizer. RESULTS: Mild improvement was seen in 46% (n=6) and moderate improvement in 16% (n=2). Fifty-four percent (n=7) of the total sample discontinued treatment because of adverse effects. CONCLUSION: Oxcarbazepine may possess mild to moderate mood-stabilizing properties in this refractory, mostly depressed, bipolar sample. This naturalistic study is limited by its uncontrolled nature
J Clin Psychopharmacol 2003 Apr;23(2):182-92 :
Antidepressant properties of anticonvulsant drugs for bipolar disorder.
Ernst CL, Goldberg JF.
Department of Psychiatry, Cambridge Hospital, Cambridge, Massachusetts, USA.
A growing number of anticonvulsant drugs are receiving attention as possible mood stabilizers. This attention is based mainly on the assumption that the antimanic efficacy of anticonvulsants makes them suitable as mood stabilizers. However, their antidepressant properties have received less scrutiny. In this review, current evidence concerning the acute and prophylactic efficacy of divalproex, carbamazepine, gabapentin, lamotrigine, and topiramate in bipolar depression is evaluated. Clinical outcome data are considered, together with limitations of existing studies and the concept of unmet clinical needs. Findings in placebo-controlled trials suggest an acute and prophylactic antidepressant effect with lamotrigine monotherapy and more modest antidepressant benefits with other agents administered as monotherapies. Results of published studies are considered with respect to the conceptualization of mood stabilization as arising from antimanic and antidepressant efficacy in bipolar disorder
Biol Psychiatry 2003 Apr 15;53(8):671-9 :
Advances in the pharmacologic treatment of bipolar depression.
Keck PE, Nelson EB, McElroy SL.
Division of Psychopharmacology Research, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
The pharmacologic treatment of bipolar depression has not been well studied in randomized, controlled trials. Thus important clinical questions regarding the efficacy in bipolar depression of mood stabilizers, antidepressants, and new antiepileptic and atypical antipsychotic agents have been relatively unaddressed. Until recently there were few data regarding the degree to which mood stabilizers reduce the risk of switching associated with antidepressant treatment. Likewise, although treatment guidelines have often recommended limiting antidepressant exposure in the maintenance treatment of bipolar depression, the potential risks of depressive relapse after antidepressant discontinuation were largely unknown. We review here data from new randomized, controlled trials published or presented during the past 5 years regarding the efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment of bipolar depression. We also review new studies clarifying the protective effect of coadministration of mood stabilizers from antidepressant-associated switching and the risk of depressive relapse when antidepressants are discontinued during maintenance treatment.
J Affect Disord 2003 Feb;73(3):223-8 :
Lithium, anticonvulsants and suicidal behavior in bipolar disorder.
Yerevanian BI, Koek RJ, Mintz J.
Ambulatory Care Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
BACKGROUND: Lithium has been found to be effective in reducing suicide rates during long term treatment of patients with bipolar disorders. Data on the efficacy of anticonvulsant mood stabilizers in reducing suicide risk are sparse. METHOD: Charts of 140 bipolar patients treated continuously for a minimum of 6 months during a 23-year period of private practice by the senior author were extracted from nearly 4000 patient records. Data extracted from the charts were incidence of completed suicide, number of suicide attempts, and number of hospitalizations for suicidal ideation or behavior per 100 patient-years of either 'on' or 'off' lithium or anticonvulsant mood stabilizer monotherapy. RESULTS: Only one completed suicide (during a period off of lithium) occurred in the patients studied. Incidence of non-lethal suicidal behavior was not different during treatment with lithium, compared with anticonvulsants. Being on a mood stabilizer significantly protected against suicidal behavior. The relative protective effect was more modest than in reports from other treatment settings. LIMITATIONS: This was a retrospective chart review study of naturalistically treated patients. CONCLUSIONS: Treatment of patients with bipolar disorder with either lithium or anticonvulsant mood stabilizers was associated with reduced risk of suicidal behavior. This study did not find evidence for a difference in the protective effect of the two types of mood stabilizing medications against non-lethal suicidal behavior in the naturalistic setting of private practice.
Actas Esp Psiquiatr 2003 Jan-Feb;31(1):40-7 :
[New treatment for bipolar disorder in children and adolescents: learning from adult studies]
[Article in Spanish]
Soutullo C, Barroilhet S, Landecho I, Ortuno F.
Background. Up to 45% of bipolar patients fail to respond adequately to or do not tolerate treatment with standard antimanics (lithium, valproate, carbamazepine, or olanzapine). Several new potential normothymic and antimanic treatments are under study. However, there is less literature available on new treatments for bipolar disorder in children and adolescents, but many youths with manic symptoms are treated with mood stabilizers. Our goal was to review the current literature on alternatives to lithium, valproate and carbamazepine in the treatment of bipolar disorder in children, adolescents and adults, focusing on the potential uses of these drugs in youth. Methods. In a comprehensive computerized and manual literature search in Medline, we identified articles, abstracts and book chapters describing new treatments for bipolar disorder in children, adolescent, and adults. We also manually searched the abstracts in recent APA, AACAP and ECNP Annual Meetings. Results. There are very few studies on the treatment of youths with bipolar disorder. The strongest evidence of antimanic action in this age group is on lithium, valproate, and recently on olanzapine, and adjunctive risperidone. Evidence on new antiepileptics and other novel treatments is very limited or none. Conclusion. More controlled studies on the treatment of children and adolescents with bipolarity are needed. Lithium, valproate, olanzapine and risperidone are probably the drugs with more evidence as antimanic efficacy in children and adolescents, but potential risks and benefits of treatment versus no treatment must be discussed with parents. Actas Esp Psiquiatr 2003;31(1):40-7
CNS Drugs 2003;17(1):9-25 :
Bipolar depression: management options.
Malhi GS, Mitchell PB, Salim S.
School of Psychiatry, University of New South Wales, Randwick, Sydney, New South Wales, Australia.
Bipolar depression is the predominant abnormal mood state in bipolar disorder. However, despite the key pertinence of this phase of the condition, the focus of research and indeed of clinical interest in the management of bipolar disorder has been mainly on mania. Bipolar depression has been largely neglected, and early studies often failed to distinguish depression due to major unipolar depression from that due to bipolar disorder. Consequently, many treatments used in the management of major depression have been adopted for use in bipolar depression without any robust evidence of efficacy. The selective serotonin reuptake inhibitors (SSRIs), bupropion, tricyclic antidepressants and monoamine oxidase inhibitors are all effective antidepressants in the management of bipolar depression. They are all associated with a small risk of antidepressant-induced mood instability. The mood stabilisers lithium, carbamazepine and valproate semisodium (divalproex sodium) all appear to have modest acute antidepressant properties. Among these, lithium is supported by the strongest data, but the use of lithium in the treatment of bipolar depression as a monotherapeutic agent is limited by its slow onset of action. Recently, there has been a growing body of evidence suggesting that lamotrigine may have particular effectiveness in both the acute and prophylactic management of bipolar depression. Clinical management of bipolar depression involves various combinations of antidepressants and mood stabilisers and is partly determined by the context in which the depressive episode occurs. In general, 'de novo' and 'breakthrough' (where the patient is already receiving medication) bipolar depression may be successfully managed by initiating mood stabiliser monotherapy, to which an antidepressant or second mood stabiliser may be added at a later date, if necessary. Breakthrough episodes of bipolar depression occurring in patients receiving combination therapy (two mood stabilisers or a mood stabiliser plus an antidepressant) require either switching of ongoing medications or further augmentation. If this fails, then novel strategies or ECT should be considered. Bipolar depression is a disabling illness and the predominant mood state for the vast majority of those with bipolar disorder. It therefore warrants prompt management once suitably diagnosed, especially as it is associated with a considerable risk of suicide and in the majority of instances is eminently treatable.
Cochrane Database Syst Rev 2003;(1):CD004052 :
Valproate for acute mood episodes in bipolar disorder.
Macritchie K, Geddes JR, Scott J, Haslam D, de Lima M, Goodwin G.
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OXON, UK, OX3 7JX. john.geddes@psych.ox.ac.uk
BACKGROUND: Bipolar disorder is a common debilitating illness, characterised by acute affective episodes with full or partial inter-episode remission. Effective and acceptable treatment of acute episodes is required. Valproate has become a leading adjunctive and alternative mood stabilising treatment to lithium in bipolar disorder. OBJECTIVES: To determine the efficacy and acceptability of valproate in the treatment of acute episodes of bipolar disorder. SEARCH STRATEGY: The search included the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registrar (CCDANCTR), the Cochrane Controlled Clinical Trials Register (CCTR), reference lists of relevant papers and books, and contact with authors of trials, experts and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing valproate with placebo, other mood stabilisers and antipsychotic medication in the treatment of any bipolar affective episode. Participants were of both sexes, of all ages, with a diagnosis of bipolar affective disorder approximating to ICD 10 Code F31 and DSM IV 296. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed independently by two reviewers blind to the authorship and source of papers. Ten randomised controlled trials were found comparing valproate with other interventions in mania. None was found examining its use in depression or mixed affective episodes. Data were extracted on the main outcome 'failure to respond by the end of the study' assessed by a less than 50% reduction in the Young Mania Rating Scale or the SADS-S mania scale. Three trials (316 participants) compared valproate with placebo. Three trials (158 participants) compared valproate with lithium. Two trials (363 participants) compared valproate with olanzapine. One trial (36 participants) compared valproate with haloperidol. Two trials (59 patients) compared valproate with carbamazepine. Acceptability of treatment was estimated using the outcome measure 'total number of subjects withdrawing from the study'. Three trials (321 patients) contributed to the comparison between valproate and placebo, two studies (144 patients) contributed to the comparison with lithium. One study (30 patients) provided data on this outcome in the comparison between valproate and carbamazepine. Pooled relative risks (with 95% confidence intervals) were calculated using fixed effect approaches. MAIN RESULTS: Valproate was more efficacious than placebo (RRR 38%; RR 0.62; 95% C.I. 0.51 to 0.77) in the treatment of mania. There was no significant difference between valproate and lithium (RRI 5%; RR 1.05; 95% C.I. 0.74-1.50) or between valproate and carbamazepine (RRR 34%; RR 0.66; 95% C.I. 0.38 to 1.16). Valproate was less effective than olanzapine (failure to achieve clinical response; RRI 25%; RR 1.25, 95% C.I. 1.01 to 1.54; average of 2.8 point less change on the Mania Rating Scale (95% CI 0.83 to 4.79). There were no significant differences in acceptability as measured by total number of subjects withdrawing from the study. There were significant differences in the side effect profiles of valproate and olanzapine, with more sedation and weight gain on olanzapine. REVIEWER'S CONCLUSIONS: There is consistent, if limited, evidence to suggest that valproate is an efficacious treatment for acute mania. Valproate may be less effective than olanzapine but may cause less sedation and weight gain. More well designed, randomised controlled trials investigating the relative efficacy and acceptability of valproate in the treatment of the full range of acute affective episodes occurring in bipolar disorder are required.
J Clin Psychopharmacol 2002 Dec;22(6):599-609 :
Review of the use of topiramate for treatment of bipolar disorders.
Suppes T.
Department of Psychiatry, Bipolar Disorder Clinic and Research Program, University of Texas Southwestern Medical Center, Dallas 75390-9070, USA.
Trisha.Suppes@UTSouthwestern.edu
Lithium alone or in combination with other psychotherapeutic drugs has long been the gold standard of management for bipolar disorder (BD). Recognition of its limitations in the acute and chronic management of BD has led to the development of alternative therapies. One such approach involves the use of antiepileptic drugs (AEDs). The AED topiramate is currently being studied in the efficacy and management of BD. Topiramate has mechanisms in common with other AEDs, including sodium channel-blocking activity and enhancement of cerebral GABA concentrations. Open-label trials have evaluated topiramate at mean daily doses of 100 to 300 mg in various BD subtypes, including acute mania, depression, rapid-cycling, mixed states, and BD refractory to other medications. Results from these trials suggest topiramate may be efficacious in BD subtypes, particularly in rapid-cycling patients and those refractory to conventional treatment. Its side effect profile appears benign when used as monotherapy or in combination with other mood stabilizers. Placebo-controlled, double-blind studies are warranted to evaluate topiramate further in BD.
Clin Ther 2002 Oct;24(10):1576-84:
Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review.
Chengappa KN, Chalasani L, Brar JS, Parepally H, Houck P, Levine J.
Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213-2593, USA.
chengappakn@msx.upmc.edu
BACKGROUND: Subsets of psychiatric patients gain excess body weight while receiving mood-stabilizing agents such as lithium carbonate or valproate sodium. Patients who gain excess weight may discontinue therapy, with severe consequences. Among the newer anticonvulsant agents, topiramate is a candidate agent for bipolar disorder and is associated with weight loss when used as adjunctive treatment. OBJECTIVE: This open-label, nonrandomized, chart-review study assessed changes in body weight and body mass index (BMI) in patients receiving topiramate, lithium, or valproate. METHODS: Data were extracted from the medical charts of patients admitted in 1999 and 2000 to a state psychiatric hospital with either schizophrenia, schizoaffective disorder, bipolar disorder, or other psychiatric diagnoses who were prescribed valproate, lithium, or topiramate and were reviewed for changes in body weight and BMI. The use of concomitant psychotropic medicines was recorded (eg, antipsychotic agents, antidepressant agents, other mood stabilizers such as gabapentin or carbamazepine). Continuous variables were analyzed using a factorial analysis of variance and the Student t test. Contingency statistics were used to analyze categorical variables. RESULTS: A total of 214 patients were included in the chart review (123 men, 91 women; mean age, 39.4 years). Significantly more women than men received topiramate (P = 0.004). Patients receiving either lithium or valproate gained a mean (SD) of 6.3 (9.0) kg and 6.4 (9.0) kg, respectively, whereas patients receiving topiramate lost a mean 1.2 (6.3) kg (F = 11.54, df = 2,198; P < 0.001). Lithium- or valproate-treated patients experienced an increase in BMI (mean, 2.1 [3.0] for both groups), whereas topiramate-treated patients experienced a reduction in BMI (mean, -0.5 [2.4]); this result was statistically significant (F = 11.40, df = 2,198; P < 0.001). Finally, lithium- or valproate-treated patients gained >8% of their baseline body weight (8.2% [11.5%] for lithium-treated patients and 8.5% [11.9%] for valproate-treated patients), whereas topiramate-treated patients lost 0.7% (7.2%) of their body weight (F = 9.93, df= 2,198; P < 0.001). CONCLUSIONS: Controlled studies for the efficacy of topiramate therapy in various psychiatric conditions are awaited. These data indicate that patients receiving topiramate experience body weight loss and a reduction in BMI. This advantage of topiramate may promote long-term adherence to treatment among psychiatric patients and possibly decrease the medical risks associated with obesity.
Prog Neuropsychopharmacol Biol Psychiatry 2002 Oct;26(6):1035-9 :
Clinical outcome of adjunctive topiramate treatment in a sample of refractory bipolar patients with comorbid conditions.
Guille C, Sachs G.
Harvard Bipolar Research Program, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Topiramate, a novel antiepileptic agent, has shown promise in the treatment of bipolar disorder. Patients attending a bipolar specialty clinic and treated with topiramate were identified by chart review, and data were harvested from systematic prospective assessments used routinely in the clinic. Fourteen patients who received topiramate for an average of 22.4 weeks were identified. All but one of these patients were considered to be highly refractory to standard treatment and 13 met the criteria for at least one comorbid psychiatric condition. Nine of these patients (64%) experienced an increased level of functioning and decrease in symptom severity during treatment with adjunctive topiramate. Eleven patients remained on treatment for longer than 2 weeks. Eight of these patients (73%) experienced a significant improvement in their comorbid conditions. Patients with a body mass index (BMI) of > or = 28 (n = 4) experienced a mean weight loss of 29.7 lb while on topiramate. Topiramate appears to be a promising agent for the treatment of bipolar disorder associated with comorbid psychiatric conditions and obesity.
Arch Gen Psychiatry 2003 Apr;60(4):392-400 :
A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.
Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J; Lamictal 606 Study Group.
Department of Psychiatry, University of Texas Health Science Center at San Antonio, 78229, USA.
bowdenc@uthscsa.edu
BACKGROUND: Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. METHODS: After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. RESULTS: Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (lamotrigine vs placebo, P =.02; lithium vs placebo, P =.006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode (P =.02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode (P =.006). The most common adverse event reported for lamotrigine was headache. CONCLUSIONS: Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.
Allergy Asthma Proc 2002 Nov-Dec;23(6):415-9 :
Prolonged anticonvulsant hypersensitivity syndrome related to lamotrigine in a patient with human immunodeficiency virus.
Beller TC, Boyce JA.
Department of Medicine and Pediatrics, Harvard Medical School, Rheumatology, Immunology and Allergy Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Anticonvulsant hypersensitivity syndrome (AHS) is a rare, potentially life-threatening allergic disorder, which is well described in relation to many aromatic anticonvulsants. Lamotrigine is a relatively new aromatic anticonvulsant agent that is thought to act on voltage-dependent sodium channels. Initially, it was licensed as add-on therapy for seizures inadequately controlled by other medications. However, its use has been broadened to other indications, including stand-alone therapy for seizures as well as for bipolar disorder. There is extensive experience with hypersensitivity syndromes related to phenytoin, carbomazepine, primidone, and phenobarbital, but fewer reactions have been reported to lamotrigine because of its relatively recent release. Patients with human immunodeficiency virus (HIV) have a higher rate of adverse reactions to many medications. It is unknown if they react more commonly to anticonvulsants such as lamotrigine. It is also unknown if the syndrome lias a tendency to be more severe or prolonged in such patients. The diagnosis of AHS may be particularly elusive in patients with HIV because its common features can easily be confused with an infectious etiology. We report the occurrence of a prolonged hypersensitivity syndrome likely related to lamotrigine in a 32-year-old female with HIV and review the literature regarding this condition.
Can J Psychiatry 2002 Oct;47(8):767-70 :
Lamotrigine use in geriatric patients with bipolar depression.
Robillard M, Conn DK.
Baycrest Centre for Geriatric Care, Department of Psychiatry, 3560 Bathurst Street, Toronto, ON M6A 2E1.
mrobillard@baycrest.org
OBJECTIVE: To study the effectiveness of adding lamotrigine to the treatment of inpatient geriatric patients with bipolar disorder (BD) who were in the depressed phase and had been on lithium and valproate for at least 3 months. METHOD: Lamotrigine was started at 25 mg given at bedtime, with weekly incremental increases of 12.5 mg daily until a total dosage of either 75 mg or 100 mg was obtained. Improvement was measured by clinical interview and Hamilton Depression Rating Scale (HDRS) scores. Patients were reassessed at 6 weeks, and if their HDRS score had decreased by at least 50%, they were considered to have improved. RESULTS: The study group comprised 5 women with an average age of 71.5 years (range 65 to 85). Four had rapid-cycling BD, and 1 had mixed BD. All patients had early age of onset, as judged by their first contact with a psychiatrist or their first hospitalization. The average initial HDRS score was 27 (range 20 to 35). Of the patients, 3 out of the 5 had remission of symptoms, as judged by clinical interview and reduction of their HDRS score by 50%. At 3 months follow-up, these 3 patients had not required rehospitalization and were doing well. Lamotrigine was well tolerated, and none of the patients developed a rash. One patient did develop coarse hand tremor that improved when the lamotrigine dosage was decreased. CONCLUSIONS: Lamotrigine in conjunction with lithium and valproate may be effective in treating geriatric patients with BD and depression.
Expert Opin Pharmacother 2002 Oct;3(10):1513-9:
Erratum in:
Expert Opin Pharmacother. 2002 Nov;3(11):1683.
Lamotrigine in the treatment of bipolar disorder.
Bowden CL.
Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Lamotrigine has undergone a remarkable series of systematic studies since 1994 that now establish it as an efficacious, well-tolerated treatment in bipolar disorder. Its efficacy principally addresses both acute and maintenance phase benefits on depressive symptomatology. These benefits have been demonstrated in placebo-controlled studies, rapid cycling patients, bipolar I and II patients and monotherapy as well as in combination therapy, although this has been less well studied. The drug is exceptionally well-tolerated in long-term treatment, although initial dosing requires gradual dosage escalation to avoid the risk of inducing serious rashes with features within the spectrum of Stevens-Johnson syndrome. Administration with valproate requires a slower dosage titration, whereas, as with many drugs, administration with carbamazepine requires a more rapid dosage increase. In contrast to marketed antidepressants, lamotrigine appears not to induce manic or hypo-manic episodes, nor to increase cycling frequency. This combination of properties makes it a first-choice treatment for acute bipolar depression and continuation treatment, especially, but not limited to, prophylaxis against recurrent depression and depressive symptoms. Lamotrigine appears not to have acute antimanic properties. A small number of studies suggest a broader spectrum of efficacy, including in some axis I disorders that are comorbidly associated with bipolar disorder.
Epilepsy Res 2002 Jun;50(1-2):195-202 :
Antiepileptic drugs in psychiatry-focus on randomized controlled trial.
Muzina DJ, El-Sayegh S, Calabrese JR.
Department of Psychiatry and Psychology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
muzinad@ccf.org
It is now clear that the class of antiepileptic drugs (AED) constitute a heterogeneous grouping of medications with diverse medical applications. In particular, the spectrum of psychiatric uses of these medications has grown substantially. Valproate and carbamazepine are commonly used in the treatment of bipolar mania, lamotrigine in bipolar depression, and gabapentin in various anxiety disorders. Only divalproex sodium and carbamazepine have received regulatory approval in various countries around the world. This article will review the double-blind, placebo-controlled literature regarding the safety and spectrum of efficacy associated with the use of the above drugs in mood and anxiety disorders.
Seizure 2002 Jan;11(1):51-6 :
Comparative bioethics in bipolar and epilepsy research.
Kaufman KR.
UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, Suite #2200, New Brunswick, NJ 08901, USA.
kaufmakr@umdnj.edu
RATIONALE: AEDs are increasingly evaluated for efficacy in bipolar disorders utilizing double-blind, placebo-controlled, randomized clinical trials (RCTs) as required by the FDA. However, the risk to patients is under-estimated in trial design. Bipolar depression has a significant risk for suicide; bipolar episodes can lead to kindling with increased long-term morbidity; rapid regression may occur during the placebo phase or during dose ranging trials with resultant active suicide status. The associated risks mandate that the ethics of FDA-required protocols are addressed. METHOD: Comparative analysis and literature review of bipolar and epilepsy research designs. RESULTS: In psychiatry, all INDs require RCTs for approval. In epilepsy, AEDs are initially approved as add-on agents only. Once AEDs have demonstrated add-on efficacy, cross-over studies comparing active AEDs, sub-optimal dosing paradigms, new-onset, and pre-surgical inpatient placebo trials are utilized to prove efficacy of the new AED in monotherapy. Ethical considerations to avoid seizures and to minimize risks to subjects have led to newer clinical trial designs. CONCLUSIONS: The FDA initially requires add-on studies with new AEDs due to the risk of seizures during the placebo phase. The author argues that bipolar research warrants similar add-on studies to prove efficacy because the risk of suicide and increased long-term morbidity in the bipolar population is as significant as the risk of seizures in the epilepsy population. Although the number of patients needed to prove statistical efficacy would increase, the safety of such research would also markedly increase. The author further concludes that with the risk of suicide during bipolar research, ethical considerations require increased frequency of patient contact with a significant other co-signing the informed consent for research and serving as a contact for the coordinator. Copyright 2002 BEA Trading Ltd.
