Kegg Pathway: Anticonvulsants

Actas Esp Psiquiatr. 2009 Jul; 37(4): 205-212
Roncero C, Rodríguez-Urrutia A, Grau-López L, Casas M

The disorders classified as control of the impulses; explosive intermittent disorder, pathological gambling, kleptomania, pyromania, pathological gambling, hair pullers, compulsive purchases, skin picking and onychophagia are a heterogeneous set of clinical entities, most of them with little prevalence. Nevertheless, they cause important personal and social dysfunctions and present great comorbidity with other psychiatric disorders. Antipsychotics, antidepressive agents, serotoninergic agonists, naltrexone, beta blockers antiandrogen, lithium and Anticonvulsants have been used in their pharmacological treatment. Currently, interest is growing on the use of the antiepileptics because their possible usefulness has been described in these disorders. However, the neurobiological effects are only partially known in some cases. We have reviewed the literature regarding the treatment of these disorders with mood stabilizers, (lithium, carbamazepine, valproate, phenitoin, oxcarbacepin, topiramate, lamotrigin, leviteracetam) and have described those studies on which the current knowledge and evidence are based. The results must be considered as provisional and must be updated in the future, since they are mostly based on case reports, case series or opened clinical trials, their being little knowledge based on double blind clinical trials. Key words:Impulse control disorders. Antiepileptic drug. Explosive intermittent disorder. Pathological gambling. Kleptomania. Pyromania. Hair pullers. Actas Esp Psiquiatr 2009;37(4):205-212.

Curr Drug Targets. 2009 Nov 1; 10(11): 1052-1060
Bourin M, Chenu F, Hascoët M

Antidepressant drugs modify in different ways the activity of neurons, by increasing monoamines levels and by modulating ion channels. Sodium channels are molecular targets for antiepileptic drugs, which can also be mood stabilizers (i.e. lamotrigine, topiramate, phenytoin, carbamazepine, valproic acid). After a short overview on the sodium channels and the interaction with antidepressants and mood stabilizers, a comparison of the activity of both antidepressants and mood stabilizers with the addition of veratrine (sodium channel opener) on the forced swimming test (FST) in mice was presented. By comparing the antidepressant-like effect of the antidepressants (paroxetine, imipramine and desipramine) with the one of Anticonvulsants (lamotrigine, phenytoin and topiramate) on the FST, it seems that the mechanism of action of Anticonvulsants and antidepressants is different, because veratrine limits the activity of Anticonvulsants but not of antidepressants. The Anticonvulsants topiramate and phenytoin reduce the immobility time in the FST in a range of time similar to that induced by antidepressants, suggesting that the FST could be sensitive to both drugs. The magnitude of antidepressant-like effect of the lamotrigine (acting through an increase in monoaminergic neurotransmission and a blockade of sodium channels) in the FST is greater than what is obtained after administration of the other drugs, suggesting that this dual activity could be used as an augmentation strategy. Authors conclude that the development of new drugs acting on sodium channels could potentially be of interest as antidepressants, but also as augmentation strategies for classical antidepressants.

Reg Anesth Pain Med. 2009 September/October; 34(5): 514-521
Benzon HT, Chekka K, Darnule A, Chung B, Wille O, Malik K

OBJECTIVE:: A patient with postherpetic neuralgia (PHN) did not respond to medications, either singly or in combination, or to intrathecal methylprednisolone but responded to intrathecal alcohol. This evidenced-based case management article evaluates and grades the evidence for the prevention and treatment of PHN. METHODS:: A search of published English-language studies on the prevention and treatment of PHN was made. RESULTS:: Randomized clinical studies showed the efficacy of antiviral agents in the prevention of PHN and the use of Anticonvulsants, antidepressants, opioids, and Lidoderm patch in the treatment of PHN (level A evidence). The role of epidural local anesthetic and steroid injections in preventing PHN has not been completely established (level B evidence). Intrathecal steroid injections and topical capsaicin may be effective in PHN (level B evidence). No randomized controlled study supports the usefulness of spinal cord stimulation and intrathecal alcohol. CONCLUSIONS:: Postherpetic neuralgia should be managed pharmacologically. If not effective, intrathecal steroid injections or nerve blocks may be tried. Spinal cord stimulation or intrathecal alcohol should be used only as a last resort.

Cutis. 2009 Oct; 84(4): 207-14
Galatian A, Stearns G, Grau R

Pruritus is a common symptom reported in connective tissue and other common systemic disease states. Unfortunately, the unique pathophysiologic etiology of the often chronic and severe pruritus that is a debilitating component of many connective tissue disorders makes treatment with conventional anti-itch agents difficult. As the underlying mechanisms of pruritus have been identified, treatment strategies have evolved. Considering the diversity of available antipruritic therapies and the variability of underlying factors specific to disease states, individualized therapy recommendations are necessary. Important new areas of treatment target the central and peripheral mechanisms of pruritus and include Anticonvulsants, antidepressants, opioid antagonists, and phototherapy Further research is necessary to quantify the role of new and novel antipruritic therapies.

Curr Opin Psychiatry. 2009 Nov 6;
Fountoulakis KN

PURPOSE OF REVIEW: The current article attempts to summarize the current status of our knowledge and practice in the treatment of bipolar depression and suggests future directions. RECENT FINDINGS: Our knowledge about lithium solidly supports its usefulness during all phases of bipolar illness and its specific effectiveness on suicidal prevention. Specific second-generation antipsychotics could constitute a promising option for treating bipolar depression, although only limited data exist so far. Anticonvulsants appear to possess a broad spectrum of effectiveness, including mixed dysphoric and rapid-cycling forms. Lamotrigine may be preferably effective in the treatment of depression but not mania. The usefulness of antidepressants in bipolar depression is controversial. The first line of psychosocial intervention in bipolar depression is psychoeducation, family-focused psychoeducation and cognitive-behavioral therapy. Electroconvulsive therapy and transcranial magnetic stimulation are options for refractory patients. Accumulated knowledge so far indicates that bipolar patients need continuous administration of an antimanic agent even during the acute depressive phase. SUMMARY: The development of rationalized 'combination treatment' guidelines is essential today, as it seems that the vast majority of patients do poorly on monotherapy and need complex pharmacotherapies. Although our knowledge is indeed limited, the development of some kind of guidelines for polypharmacy is possible and should be done as soon as possible.

J Feline Med Surg. 2009 Nov 6;
Boland LA, Angles JM

Forty-two cases of feline permethrin toxicity treated at a referral hospital in Sydney, Australia were retrospectively reviewed. In most cases canine permethrin spot-on (PSO) flea products had been directly applied to affected cats. Most presented during summer and there was an increase in cases during the 2007/2008 period. Clinical signs included; tremors/muscle fasciculations (86%), twitches (41%), hyperaesthesia (41%), seizures (33%), pyrexia (29%), ptyalism (24%), ataxia (24%), mydriasis (19%) and temporary blindness (12%). Treatment involved decontamination, Anticonvulsants and supportive care. Methocarbamol was not used. Complications occurred in 33% of cats and included: hypothermia (29%), electrolyte abnormalities (26%), aspiration pneumonia (12%), hypoproteinaemia (12%), anaemia (5%), apnoea (7%), respiratory arrest (5%), cardiorespiratory arrest (2%), pleural effusion (2%), urinary tract infection (2%) and corneal ulceration (2%). One cat was euthanased. Feline permethrin toxicity may result in severe clinical signs requiring intensive treatment. Despite prominent label warnings, cases of feline permethrin toxicity continue to occur in Australia and may be fatal.

Neurology. 2009 Nov 3; 73(18): 1512; author reply 1512-3
Freeman WD, Barrett KM, Freeman ML, Johnson M, Divertie G, Rossetti AO, Kaplan PW

Am J Psychiatry. 2009 Nov; 166(11): 1217-21
Sharma V, Burt VK, Ritchie HL

Research on postpartum mood disorders has focused primarily on major depressive disorder, bipolar I disorder, and puerperal psychosis and has largely ignored or neglected bipolar II disorder. Hypomanic symptoms are common after delivery but frequently unrecognized. DSM-IV does not consider early postpartum hypomania as a significant diagnostic feature. Although postpartum hypomania may not cause marked impairment in social or occupational functioning, it is often associated with subsequent, often disabling depression. Preliminary evidence suggests that bipolar II depression arising in the postpartum period is often misdiagnosed as unipolar major depressive disorder. The consequences of the misdiagnosis can be particularly serious because of delayed initiation of appropriate treatment and the inappropriate prescription of antidepressants. Moreover, no pharmacological or psychotherapeutic studies of bipolar postpartum depression are available to guide clinical decision making. Also lacking are screening instruments designed specifically for use before or after delivery in women with suspected bipolar depression. It is recommended that the treatment of postpartum bipolar depression follow the same guidelines as the treatment of nonpuerperal bipolar II depression, using medications that are compatible with lactation.

Am J Psychiatry. 2009 Nov; 166(11): 1209-10
Brady KT

J Rehabil Res Dev. 2009; 46(4): 463-8
French DD, Bair MJ, Bass E, Campbell RR, Siddharthan K

Little is known about the utilization of central nervous system (CNS) and musculoskeletal (MS) medications in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans with blast-related injuries (BRIs). We followed prescription drug use among a cohort of 133 OIF/OEF veterans with BRIs by using the Joint Theatre Trauma Registry, the Tampa Polytrauma Registry, and electronic medical records. We extracted 12 months of national medication records from the Veterans Health Administration Decision Support System and analyzed them with descriptive statistics. Over the 12-month period (fiscal year 2007), CNS medications comprised 27.9% (4,225/15,143) of total prescriptions dispensed to 90.2% (120/133) of our cohort. Approximately one-half (48.9%) of the 133 patients were treated with opioid analgesics. Nearly 60% received antidepressants. More than one-half (51.1%) of patients were treated with Anticonvulsants. Benzodiazepines and antipsychotics were dispensed to 17.3% and 15.8%, respectively. For MS medicines, 804 were prescribed for 48.1% (64/133) of veterans. Nearly one-fourth (24.8%) were treated with skeletal muscle relaxants. The CNS and MS medications, in general, were continuously prescribed over the 12-month study period. This study provides insight into the complex medical management involved in the care of veterans with BRIs.

Brain Behav Immun. 2009 Oct 29;
Busch-Dienstfertig M, Stein C

This review summarizes recent findings on neuro-immune mechanisms underlying opioid-mediated inhibition of pain. The focus is on events occurring in peripheral injured tissues that lead to the sensitization and excitation of primary afferent neurons, and on the modulation of such mechanisms by immune cell-derived opioid peptides. Primary afferent neurons are of particular interest from a therapeutic perspective because they are the initial generators of impulses relaying nociceptive information towards the spinal cord and the brain. Thus, if one finds ways to inhibit the sensitization and/or excitation of peripheral sensory neurons, subsequent central events such as wind-up, sensitization and plasticity may be prevented. This is in part achieved by endogenously released immune cell-derived opioid peptides within inflamed tissue. In addition, exogenous opioid receptor ligands that selectively modulate primary afferent function and do not cross the blood-brain barrier, avoid centrally mediated untoward side effects of conventional analgesics (e.g., opioids, Anticonvulsants). This article discusses peripheral opioid receptors and their signaling pathways, opioid peptide-producing/secreting inflammatory cells and arising therapeutic perspectives.

Arch Iran Med. 2009 Nov; 12(6): 550-4
Ashjazadeh N, Zamani A, Pourjafar M, Omrani GR

BACKGROUND: Chronic antiepileptic therapy has been associated with metabolic bone diseases including osteomalacia and osteoporosis. The object of this study was to assess the effect of first line Anticonvulsants on bone density and vitamin D levels in Iranian ambulatory patients. METHODS: We conducted a cross-sectional study assessing bone density with dual energy X-ray absorptiometry at the hip and lumbar spine in 90 outpatients receiving Anticonvulsants and 90 normal subjects matched for age, sex, and body mass index. Plasma total calcium, intact parathyroid hormone, total alkaline phosphatase in addition to 25 hydroxy vitamin D were also determined in both groups. RESULTS: The mean (+/-SD) bone density in patients treated with antiepileptic drugs was lower at the spine (T Score= -084+/-1.18 vs. -0.5+/-1.18, P< 0.05) and femoral neck (T Score= -0.83+/-1.11 vs. -0.46+/-1.1, P<0.05), compared to the control group of subjects. In addition, serum total alkaline phosphatase was significantly higher in patients (246.5+/-127 vs. 190+/-65.3, P=0.004), but the total calcium, parathyroid hormone and 25 hydroxy vitamin D did not differ significantly between patients and controls. CONCLUSION: Our results suggest that maintenance therapy with antiepileptic drugs may decrease bone mass. These data also suggest a higher bone turnover rate in those receiving Anticonvulsants.

Nucl Med Biol. 2009 Nov; 36(8): 949-54
Yamada A, Momosaki S, Hosoi R, Abe K, Yamaguchi M, Inoue O

Enhancement of glucose utilization in the brain has been well known during acute seizure in various kinds of animal model of epilepsy. This enhancement of glucose utilization might be related to neural damage in these animal models. Recently, we found that methyl ethyl ketone (MEK) had both anticonvulsive and neuroprotective effects in lithium-pilocapine (Li-pilo) status epilepticus (SE) rat. In this article, we measured the uptake of [(14)C]2-deoxyglucose ([(14)C]DG) in the Li-pilo SE and Li-pilo SE with MEK rat brain in order to assess whether the glucose utilization was a useful biomarker for the detection of efficacy of anticonvulsive compounds. Significant increase of [(14)C]DG uptake (45 min after the injection) in the cerebral cortex, hippocampus, amygdala and thalamus during acute seizure induced by Li-pilo were observed. On the other hand, the initial uptake of [(14)C]DG (1 min after the injection) in the Li-pilo SE rats was not different from the control rats. Therefore, the enhancement of glucose metabolism during acute seizure was due to the facilitation of the rate of phosphorylation process of [(14)C]DG in the brain. Pretreatment with MEK (8 mmol/kg) completely abolished the enhancement of glucose utilization in the Li-pilo SE rats. The present results indicated that glucose utilization in the brain during acute seizure might be a useful biomarker for the evaluation of efficacy of anticonvulsive compounds.

Clin Exp Dermatol. 2009 Oct 23;
Teraki Y, Shibuya M, Izaki S

Summary Background. Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to Anticonvulsants display similar clinical and laboratory features to those seen in DIHS. Methods. Patients diagnosed with SJS or TEN due to Anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant-related DIHS (n = 6). Results. Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting Anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV-6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. Conclusions. SJS/TEN due to Anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS.

Epilepsy Res. 2009 Oct 23;
Cross JH

Use of medication with a desired effect on the central nervous system (as with anti-epileptic drugs) in children will undoubtedly cause concern about neurodevelopment. Data are emerging to suggest an effect of Anticonvulsants on the developing brain of the unborn child when administered to mothers with epilepsy. This obviously requires detailed evaluation, especially when considering the risks of epilepsy itself. In the child with epilepsy, many of the early onset epilepsies are associated with developmental compromise as part of their clinical profile, and therefore determining the relative effects of the underlying cause, seizures and medication can be difficult. Although data are available with regard to some anti-epileptic drugs (AEDs) they remain lacking particularly in the very young with regard to efficacy as well as neurodevelopmental effects of the newer anti-epileptic drugs. Ongoing evaluation is required to ensure the best clinical practice in each individual.

Clin Toxicol (Phila). 2009 Nov; 47(9): 899-901
Parbhu B, Rodgers G, Sullivan JE

INTRODUCTION: Endosulfan, an organochlorine insecticide widely used in agriculture, is rapidly absorbed following ingestion, inhalation, or skin exposure. Poisonings rarely result in morbidity and mortality. Symptoms occur rapidly following exposure with CNS toxicity. Endosulfan has been banned in many countries; however, it is still used in the United States. CASE REPORT: A 2.5-year-old ingested an unknown amount of endosulfan from a 20-ounce soft drink bottle. He immediately developed generalized tonic-clonic seizure activity and became unresponsive. He was transferred to the local hospital and to a tertiary children's hospital where the seizures were refractory to treatment despite treatment with multiple Anticonvulsants. He became hypotensive requiring vasopressors. On day 3, an MRI showed cerebral edema, and a nuclear medicine flow scan failed to show blood flow to the brain and he was pronounced dead. DISCUSSION: This is the first published pediatric death in the United States because of endosulfan. Central nervous system stimulation is frequently the presenting symptom with or without other organ dysfunction. Status epilepticus causes the highest morbidity and mortality, therefore prompt administration of anticonvulsant drugs is important although not always effective. The child is our case demonstrated the most severe features of endosulfan exposure. CONCLUSION: In summary, prevention of a potentially toxic exposure is critical. The presence of this substance in a soft drink bottle contributed to the toxic exposure in this child, thus emphasizing the need for poison prevention education. The severe toxicity to those exposed raises the question of the need of this compound on the U.S. market.

N Z Med J. 2009; 122(1303): 102-4
Betteridge T, Fink J

A 48-year-old woman with known epilepsy presented to the Emergency Department with a 1-day history of decreasing coordination, impaired speech, and recurrent falls. Phenytoin levels were measured and found to be grossly elevated at 170 mmol/L. A diagnosis of phenytoin toxicity was made and she was treated by withdrawing the medication. During admission she was found to be profoundly hypothyroid despite being on adequate thyroid replacement therapy. Normalisation of phenytoin levels was associated with return of euthyroidism. The interaction between phenytoin, thyroid function, and thyroid replacement therapy is discussed.

J Neurosci. 2009 Oct 21; 29(42): 13401-9
Yasaka T, Hughes DI, Polgár E, Nagy GG, Watanabe M, Riddell JS, Todd AJ

Pure NMDA receptor (NMDAr)-mediated EPSCs, thought to correspond to "silent" glutamatergic synapses that lack AMPA receptors (AMPArs), have been observed in superficial spinal dorsal horn of neonatal but not adult rats. Recent anatomical studies suggest that AMPArs are present at virtually all glutamatergic synapses in this region in adults. We used antigen retrieval to examine colocalization of AMPArs and PSD-95 (a marker for glutamatergic synapses) in laminae I-II of neonatal and adult rats. We found a high degree of colocalization in all cases, which suggests that AMPArs are present in the great majority of glutamatergic synapses even in neonatal animals. We therefore reexamined evidence for silent synapses by performing blind whole-cell recordings from superficial dorsal horn neurons in slices from neonatal or adult rats, with focal stimulation to activate glutamatergic synapses. On some occasions in both neonatal (10 of 109, 9%) and adult (9 of 77, 12%) slices, NMDAr-mediated EPSCs were observed when the holding potential was raised to +50 mV at a stimulus strength that had failed to evoke AMPAr-mediated EPSCs. However, in all cases tested, AMPAr-mediated EPSCs were then observed when the cell was returned to -70 mV; this and other properties of the EPSCs suggest that they do not represent genuine silent synapses. When compared with previous findings, our results indicate that the appearance of silent synapses depends on experimental protocol. This suggests that pure NMDAr-mediated EPSCs seen in previous studies do not correspond to AMPAr-lacking synapses but result from another mechanism, for example, loss of labile AMPArs from recently formed synapses.

J Neurosci. 2009 Oct 21; 29(42): 13222-31
Zhang SY, Xu M, Miao QL, Poo MM, Zhang XH

Homeostatic regulation of synaptic strength in response to persistent changes of neuronal activity plays an important role in maintaining the overall level of circuit activity within a normal range. Absence of miniature EPSCs (mEPSCs) for a few hours is known to cause upregulation of excitatory synaptic strength, suggesting that mEPSCs contribute to the maintenance of excitatory synaptic functions. In the present study, we found that the absence of mEPSCs for 1-3 h also resulted in homeostatic suppression of presynaptic functions of inhibitory synapses in acute cortical slices from juvenile rats, as suggested by the reduced frequency (but not amplitude) of miniature IPSCs (mIPSCs) as well as the reduced amplitude of IPSCs. This homeostatic regulation depended on endocannabinoid (eCB) signaling, because blockade of either the activation of cannabinoid type-1 receptors (CB1Rs) or the synthesis of its endogenous ligand 2-arachidonoylglycerol (2-AG) abolished the suppression of inhibitory synapses caused by the absence of mEPSCs. Blockade of group I metabotropic glutamate receptors (mGluR-I) also abolished the suppression of inhibitory synapses, consistent with the mGluR-I requirement for eCB synthesis and release in cortical synapses. Furthermore, this homeostatic regulation also required eukaryotic elongation factor-2 (eEF2)-dependent protein synthesis, but not gene transcription. Activation of eEF2 alone was sufficient to suppress the mIPSC frequency, an effect abolished by inhibiting CB1Rs. Thus, mEPSCs contribute to the maintenance of inhibitory synaptic function and the absence of mEPSCs results in presynaptic suppression of inhibitory synapses via protein synthesis-dependent elevation of eCB signaling.

Br J Pharmacol. 2009 Nov; 158(6): 1413-25
England S, de Groot MJ

Voltage-gated sodium channels are key to the initiation and propagation of action potentials in electrically excitable cells. Molecular characterization has shown there to be nine functional members of the family, with a high degree of sequence homology between the channels. This homology translates into similar biophysical and pharmacological properties. Confidence in some of the channels as drug targets has been boosted by the discovery of human mutations in the genes encoding a number of them, which give rise to clinical conditions commensurate with the changes predicted from the altered channel biophysics. As a result, they have received much attention for their therapeutic potential. Sodium channels represent well-precedented drug targets as antidysrhythmics, Anticonvulsants and local anaesthetics provide good clinical efficacy, driven through pharmacology at these channels. However, electrophysiological characterization of clinically useful compounds in recombinant expression systems shows them to be weak, with poor selectivity between channel types. This has led to the search for subtype-selective modulators, which offer the promise of treatments with improved clinical efficacy and better toleration. Despite developments in high-throughput electrophysiology platforms, this has proven very challenging. Structural biology is beginning to offer us a greater understanding of the three-dimensional structure of voltage-gated ion channels, bringing with it the opportunity to do real structure-based drug design in the future. This discipline is still in its infancy, but developments with the expression and purification of prokaryotic sodium channels offer the promise of structure-based drug design in the not too distant future.