Introduction:
This SOAP paper focuses on the use of anti-epileptic drugs used for anti-psychotic purposes, and in some cases the anti-psychotic drugs being used for epilepsy. Interestingly, epilepsy and psychological symptoms do go hand in hand, which may give a window into why they can be used interchangeably. Also, the wide ranges of uses for anti-epileptic drugs are explored to gain an understanding why doctors are prescribing these drugs to patients who do not have epilepsy. In conclusion, the implications of using these drugs interchangeably.
Use of psychotropic drugs in patients with epilepsy: interactions and seizure risk.
Mula M, Monaco F, Trimble MR.
It is now accepted that patients with epilepsy are more prone than the general population to develop psychiatric disorders, being significantly at risk due to psychosocial reasons, the presence of electrophysiologic and anatomopathologic abnormalities mainly in the limbic system, and because they are taking antiepileptic drugs which may have negative psychotropic effects. It is also known that many patients with epilepsy sometimes receive psychotropic medications on account of their psychiatric symptoms. This review focuses on the main problems that a clinician may encompass when treating psychiatric disorders in patients with epilepsy. On one hand, the effects of antiepileptic drugs on mood and behavior for a correct differential diagnosis of psychiatric symptoms. On the other hand, the main factors that may affect choice of therapy, patients' response and compliance, when prescribing antidepressants or antipsychotic drugs, drug interactions and the potential proconvulsive risk are reviewed.
Mula M, Monaco F, Trimble MR.
It is now accepted that patients with epilepsy are more prone than the general population to develop psychiatric disorders, being significantly at risk due to psychosocial reasons, the presence of electrophysiologic and anatomopathologic abnormalities mainly in the limbic system, and because they are taking antiepileptic drugs which may have negative psychotropic effects. It is also known that many patients with epilepsy sometimes receive psychotropic medications on account of their psychiatric symptoms. This review focuses on the main problems that a clinician may encompass when treating psychiatric disorders in patients with epilepsy. On one hand, the effects of antiepileptic drugs on mood and behavior for a correct differential diagnosis of psychiatric symptoms. On the other hand, the main factors that may affect choice of therapy, patients' response and compliance, when prescribing antidepressants or antipsychotic drugs, drug interactions and the potential proconvulsive risk are reviewed.
Curr Opin Neurol. 2005 Apr;18(2):129-33
Diagnosis and treatment of mood disorders in persons with epilepsy.
Gilliam FG.
PURPOSE OF REVIEW: Epilepsy is a common, disabling neurological disorder associated with increased rates of comorbid psychiatric disorders as compared with the general population. RECENT FINDINGS: Mood disorders, especially major depression, appear to be more prevalent in persons with epilepsy than in those with the other chronic disorders and the general population. Depression may have more influence on quality of life than do cognitive and seizure factors. Although psychological, social, and vocational disabilities contribute to mood dysfunction in epilepsy, functional neuroimaging studies have consistently shown correlation of presence of cerebral abnormalities with increased severity of symptoms of depression. Most persons with epilepsy are not routinely screened for depression, and depression is subsequently treated in only a minority of patients. Although serotonin receptor density is greatest in brain regions commonly associated with epilepsy, such as the mesial temporal and prefrontal areas, no controlled trials have investigated the efficacy of serotonin reuptake inhibitors in persons with epilepsy. Optimal methods to identify and treat depression in epilepsy require substantial further research. SUMMARY: Depression is a common comorbid condition with significant negative effects on health status in persons with epilepsy, but additional understanding of the disorder is needed to improve diagnosis and treatment.
Diagnosis and treatment of mood disorders in persons with epilepsy.
Gilliam FG.
PURPOSE OF REVIEW: Epilepsy is a common, disabling neurological disorder associated with increased rates of comorbid psychiatric disorders as compared with the general population. RECENT FINDINGS: Mood disorders, especially major depression, appear to be more prevalent in persons with epilepsy than in those with the other chronic disorders and the general population. Depression may have more influence on quality of life than do cognitive and seizure factors. Although psychological, social, and vocational disabilities contribute to mood dysfunction in epilepsy, functional neuroimaging studies have consistently shown correlation of presence of cerebral abnormalities with increased severity of symptoms of depression. Most persons with epilepsy are not routinely screened for depression, and depression is subsequently treated in only a minority of patients. Although serotonin receptor density is greatest in brain regions commonly associated with epilepsy, such as the mesial temporal and prefrontal areas, no controlled trials have investigated the efficacy of serotonin reuptake inhibitors in persons with epilepsy. Optimal methods to identify and treat depression in epilepsy require substantial further research. SUMMARY: Depression is a common comorbid condition with significant negative effects on health status in persons with epilepsy, but additional understanding of the disorder is needed to improve diagnosis and treatment.
Uses of Anti-Epileptic Drugs for Psychotic Disorders:
Encephale. 1975;1(1):25-31.
Dipropylacetamide in the treatment of manic-depressive psychosis
Lambert PA, Carraz G, Borselli S, Bouchardy M.
Dipropylacetamide, which was first used as a treatment of epilepsy, turned out to be also a normalizing agent of the periodic avolution of manic-depressive psychosis. The therapeutic action of dipropylacetamide has several effects: 1) total suppression of the fits; 2) reduced intensity of these fits; 3) increasing lapse of time between two fits; 4) greatest response to anti-depressants and neuroleptics which can be prescribed in much smaller doses. More manic than depressive states respond to dipropylacetamide. The average doses are about 900 mg or so. Cautiousness if advisable at the beginning of the treatment on account of the use of sedatives; but the treatment is extremely well received and accepted by the patients during periods of several years without the requirement of biological controls. Associating lithium with dipropylacetamide often yields remarkable results.
Dipropylacetamide in the treatment of manic-depressive psychosis
Lambert PA, Carraz G, Borselli S, Bouchardy M.
Dipropylacetamide, which was first used as a treatment of epilepsy, turned out to be also a normalizing agent of the periodic avolution of manic-depressive psychosis. The therapeutic action of dipropylacetamide has several effects: 1) total suppression of the fits; 2) reduced intensity of these fits; 3) increasing lapse of time between two fits; 4) greatest response to anti-depressants and neuroleptics which can be prescribed in much smaller doses. More manic than depressive states respond to dipropylacetamide. The average doses are about 900 mg or so. Cautiousness if advisable at the beginning of the treatment on account of the use of sedatives; but the treatment is extremely well received and accepted by the patients during periods of several years without the requirement of biological controls. Associating lithium with dipropylacetamide often yields remarkable results.
Clin EEG Neurosci. 2004 Jan;35(1):53-68
Affective disorder and epilepsy comorbidity: implications for development of treatments, preventions and diagnostic approaches.
Jobe PC.
Concepts pertaining to affective disorder and epilepsy comorbidity are contributing appreciably to improvements in patient care. Several antiepileptic treatments have become important components of the management of bipolar affective disorder. In contrast, little progress has emerged in developing clinical applications of the anticonvulsant properties of the antidepressants in the treatment of the epilepsies. The slow onset of action of the antidepressants remains a major impediment to fully effective treatment of depressive episodes. Nevertheless, studies from experimental epileptology demonstrate that the anticonvulsant effects of the antidepressants occur rapidly and as a consequence of noradrenergic and/or serotonergic activation. These studies also demonstrate that adequate initial doses of the antidepressants are essential to rapid onset of anticonvulsant action. Pharmacokinetically valid loading dose paradigms are seemingly avoided with antidepressant drugs in humans because of potential toxicities and/or patient unacceptability. However, substantial progress has been made in reducing the adverse effect liability of the antidepressants. No longer is convulsive liability considered to stem from the therapeutic mechanisms of the anti-depressants. Rather, noradrenergic and serotonergic influences have demonstrable anticonvulsant properties. Other side effects may also be separable from the anticonvulsant and antidepressive effects of antidepressive treatments. The concept that the protracted process of antidepressant-induced beta-noradrenergic down-regulation is an essential prelude to the onset of mood benefit is no longer a sustainable premise. Nevertheless, increasing evidence underlies the possibility that knowledge of serotonergic and noradrenergic regulatory processes can be used to design strategies that will hasten the onset of antidepressive action. Similar optimism pervades efforts to determine the possibility that dual inhibition of serotonin and norepinephrine transporters will hasten onset of antidepressive action. Moreover, because noradrenergic and serotonergic systems are determinants of predisposition to seizures and to dysfunctional affective episodes, augmentation strategies may also be applicable to the use of antidepressant drugs in epilepsy and to the use of antiepileptic drugs such as carbamazepine in mood disorders. Recent studies have demonstrated that, in part, the therapeutic effectiveness of carbamazepine may stem from its marked capacity to elevate serotonin concentrations in the extracellular fluid of the brain via mechanisms that differ from those of the membrane reuptake inhibitors. Evidence suggests that the epilepsies and affective disorders may arise from a multiplicity of neurobiological abnormalities. A disorder in one individual may arise via different mechanisms than a phenomenologically similar disorder in another individual. Thus, diagnostic tools are needed to make mechanistic distinctions among individuals so that treatments can be appropriately developed and selected. In terms of epileptogenesis and affective disorder progression, neuroprotective paradigms for one individual may differ from those needed for another. Moreover, diagnostic technologies that are adequate to detect genetically and/or experientially determined vulnerability before the onset of a seizure or dysfunctional affective episode may be valuable steps toward achieving goals of prevention.
Affective disorder and epilepsy comorbidity: implications for development of treatments, preventions and diagnostic approaches.
Jobe PC.
Concepts pertaining to affective disorder and epilepsy comorbidity are contributing appreciably to improvements in patient care. Several antiepileptic treatments have become important components of the management of bipolar affective disorder. In contrast, little progress has emerged in developing clinical applications of the anticonvulsant properties of the antidepressants in the treatment of the epilepsies. The slow onset of action of the antidepressants remains a major impediment to fully effective treatment of depressive episodes. Nevertheless, studies from experimental epileptology demonstrate that the anticonvulsant effects of the antidepressants occur rapidly and as a consequence of noradrenergic and/or serotonergic activation. These studies also demonstrate that adequate initial doses of the antidepressants are essential to rapid onset of anticonvulsant action. Pharmacokinetically valid loading dose paradigms are seemingly avoided with antidepressant drugs in humans because of potential toxicities and/or patient unacceptability. However, substantial progress has been made in reducing the adverse effect liability of the antidepressants. No longer is convulsive liability considered to stem from the therapeutic mechanisms of the anti-depressants. Rather, noradrenergic and serotonergic influences have demonstrable anticonvulsant properties. Other side effects may also be separable from the anticonvulsant and antidepressive effects of antidepressive treatments. The concept that the protracted process of antidepressant-induced beta-noradrenergic down-regulation is an essential prelude to the onset of mood benefit is no longer a sustainable premise. Nevertheless, increasing evidence underlies the possibility that knowledge of serotonergic and noradrenergic regulatory processes can be used to design strategies that will hasten the onset of antidepressive action. Similar optimism pervades efforts to determine the possibility that dual inhibition of serotonin and norepinephrine transporters will hasten onset of antidepressive action. Moreover, because noradrenergic and serotonergic systems are determinants of predisposition to seizures and to dysfunctional affective episodes, augmentation strategies may also be applicable to the use of antidepressant drugs in epilepsy and to the use of antiepileptic drugs such as carbamazepine in mood disorders. Recent studies have demonstrated that, in part, the therapeutic effectiveness of carbamazepine may stem from its marked capacity to elevate serotonin concentrations in the extracellular fluid of the brain via mechanisms that differ from those of the membrane reuptake inhibitors. Evidence suggests that the epilepsies and affective disorders may arise from a multiplicity of neurobiological abnormalities. A disorder in one individual may arise via different mechanisms than a phenomenologically similar disorder in another individual. Thus, diagnostic tools are needed to make mechanistic distinctions among individuals so that treatments can be appropriately developed and selected. In terms of epileptogenesis and affective disorder progression, neuroprotective paradigms for one individual may differ from those needed for another. Moreover, diagnostic technologies that are adequate to detect genetically and/or experientially determined vulnerability before the onset of a seizure or dysfunctional affective episode may be valuable steps toward achieving goals of prevention.
J Neuropsychiatry Clin Neurosci. 2005 Winter;17(1):20-8.
Mood disorders and their treatment in patients with epilepsy.
Prueter C, Norra C.
Mood disorders in patients with epilepsy are not frequently diagnosed and not treated. Because of the high prevalence of depression and the resulting high suicide rate, precise diagnosis and effective therapy are very important. Frequently, the clinical pictures of depressive syndromes in epileptics do not correspond with those described in operationalized classification systems such as ICD-10 or DSM-IV. The incidence of depressive disorders in epileptics is estimated in the literature to be 30%-70%. Multifactorial pathogenetic models include the type of seizures, the location of the epileptic focus, and neurotransmitter dysfunctions, as well as hereditary and psychosocial influences, and negative psychotropic effects of antiepileptic drugs. Despite an insufficient number of available controlled studies, based on the current data, treatment with the newer serotonergic antidepressants can be recommended for patients with epilepsy.
Mood disorders and their treatment in patients with epilepsy.
Prueter C, Norra C.
Mood disorders in patients with epilepsy are not frequently diagnosed and not treated. Because of the high prevalence of depression and the resulting high suicide rate, precise diagnosis and effective therapy are very important. Frequently, the clinical pictures of depressive syndromes in epileptics do not correspond with those described in operationalized classification systems such as ICD-10 or DSM-IV. The incidence of depressive disorders in epileptics is estimated in the literature to be 30%-70%. Multifactorial pathogenetic models include the type of seizures, the location of the epileptic focus, and neurotransmitter dysfunctions, as well as hereditary and psychosocial influences, and negative psychotropic effects of antiepileptic drugs. Despite an insufficient number of available controlled studies, based on the current data, treatment with the newer serotonergic antidepressants can be recommended for patients with epilepsy.
Epilepsia. 2005 Mar;46(3):344-55.
Pharmacodynamic and pharmacokinetic interaction studies of loreclezole with felbamate, lamotrigine, topiramate, and oxcarbazepine in the mouse maximal electroshock seizure model.
Luszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ.
PURPOSE: The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis. METHODS: Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established. RESULTS: With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task. CONCLUSIONS: LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.
Pharmacodynamic and pharmacokinetic interaction studies of loreclezole with felbamate, lamotrigine, topiramate, and oxcarbazepine in the mouse maximal electroshock seizure model.
Luszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ.
PURPOSE: The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis. METHODS: Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established. RESULTS: With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task. CONCLUSIONS: LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.
Brain Res. 2005 Feb 1;1033(1):90-5.
Anticonvulsant effects of acute and repeated fluoxetine treatment in unstressed and stressed mice.
Pericic D, Lazic J, Svob Strac D.
Comorbidity of epilepsy and depression is not rare. Stress can affect both depression and seizures. Therefore, it is important to know whether an antidepressant drug has pro- or anticonvulsant properties and whether these properties will be modified by stress. We tested the effects of the antidepressant drug fluoxetine on the seizure threshold for picrotoxin in unstressed and swim-stressed mice. The mice were, prior to exposure to swim stress and the intravenous infusion of picrotoxin (a non-competitive GABA(A) receptor antagonist), pretreated with fluoxetine (a selective serotonin reuptake inhibitor), either acutely or repeatedly (5 days), and the latency to the onset of two convulsant signs and death was registered. The convulsant signs were running/bouncing clonus and tonic hindlimb extension. As expected, swim stress enhanced the seizure threshold for picrotoxin. Fluoxetine (20 mg/kg ip) given acutely increased in unstressed and swim-stressed mice the dose of picrotoxin producing tonic hindlimb extension and in unstressed mice the dose of picrotoxin producing death. Neither 10 nor 20 mg/kg of fluoxetine affected doses of picrotoxin needed to produce running bouncing/clonus. Repeated treatment with fluoxetine (20 mg/kg ip) enhanced significantly in unstressed and swim-stressed mice doses of picrotoxin needed to produce tonic hindlimb extension and death, and in stressed mice also the dose of picrotoxin producing running/bouncing clonus. The results demonstrate that the antidepressant drug fluoxetine, given acutely or repeatedly, shows anticonvulsant properties against convulsions induced in unstressed and swim-stressed mice by antagonist of GABA(A) receptors, picrotoxin. Swim stress failed to modify the anticonvulsant properties of fluoxetine.
Anticonvulsant effects of acute and repeated fluoxetine treatment in unstressed and stressed mice.
Pericic D, Lazic J, Svob Strac D.
Comorbidity of epilepsy and depression is not rare. Stress can affect both depression and seizures. Therefore, it is important to know whether an antidepressant drug has pro- or anticonvulsant properties and whether these properties will be modified by stress. We tested the effects of the antidepressant drug fluoxetine on the seizure threshold for picrotoxin in unstressed and swim-stressed mice. The mice were, prior to exposure to swim stress and the intravenous infusion of picrotoxin (a non-competitive GABA(A) receptor antagonist), pretreated with fluoxetine (a selective serotonin reuptake inhibitor), either acutely or repeatedly (5 days), and the latency to the onset of two convulsant signs and death was registered. The convulsant signs were running/bouncing clonus and tonic hindlimb extension. As expected, swim stress enhanced the seizure threshold for picrotoxin. Fluoxetine (20 mg/kg ip) given acutely increased in unstressed and swim-stressed mice the dose of picrotoxin producing tonic hindlimb extension and in unstressed mice the dose of picrotoxin producing death. Neither 10 nor 20 mg/kg of fluoxetine affected doses of picrotoxin needed to produce running bouncing/clonus. Repeated treatment with fluoxetine (20 mg/kg ip) enhanced significantly in unstressed and swim-stressed mice doses of picrotoxin needed to produce tonic hindlimb extension and death, and in stressed mice also the dose of picrotoxin producing running/bouncing clonus. The results demonstrate that the antidepressant drug fluoxetine, given acutely or repeatedly, shows anticonvulsant properties against convulsions induced in unstressed and swim-stressed mice by antagonist of GABA(A) receptors, picrotoxin. Swim stress failed to modify the anticonvulsant properties of fluoxetine.
Psychopharmacology (Berl). 1995 Apr;118(3):305-9.
Prolonged but not acute fluoxetine administration produces its inhibitory effect on hippocampal seizures in rats.
Wada Y, Shiraishi J, Nakamura M, Hasegawa H.
This study assessed the effects of acute as well as long-term administration of fluoxetine, a selective serotonin (5-HT) reuptake inhibitor with anti-depressant properties, on hippocampal (HIP) seizures elicited by electrical stimulation in rats. The fluoxetine effect on HIP seizures was also assessed following long-term treatment with gepirone, a 5-HT1A receptor agonist. Acute single administration of fluoxetine (1, 10 mg/kg; IP) was found to produce no significant effect on HIP seizure activity. Following daily IP administration of fluoxetine (10 mg/kg per day) or gepirone (10 mg/kg per day) for 21 days, animals were given a 7-day drug-free period and then challenged with an acute dose of 10 mg/kg fluoxetine. These treatment regimens resulted in a significantly increased afterdischarge threshold of HIP seizures in response to acute fluoxetine administration. The inhibitory effect of fluoxetine, however, was not present 4 weeks after long-term treatment with either fluoxetine or gepirone. The present results indicate that long-term treatment with these compounds enhances the antiepileptic effect of subsequent fluoxetine administration on the generation of HIP seizures. This effect is possibly related to the well-demonstrated evidence that fluoxetine and gepirone, on long-term treatment, facilitate net 5-HT neurotransmission through desensitization of presynaptic 5-HT autoreceptors.
Prolonged but not acute fluoxetine administration produces its inhibitory effect on hippocampal seizures in rats.
Wada Y, Shiraishi J, Nakamura M, Hasegawa H.
This study assessed the effects of acute as well as long-term administration of fluoxetine, a selective serotonin (5-HT) reuptake inhibitor with anti-depressant properties, on hippocampal (HIP) seizures elicited by electrical stimulation in rats. The fluoxetine effect on HIP seizures was also assessed following long-term treatment with gepirone, a 5-HT1A receptor agonist. Acute single administration of fluoxetine (1, 10 mg/kg; IP) was found to produce no significant effect on HIP seizure activity. Following daily IP administration of fluoxetine (10 mg/kg per day) or gepirone (10 mg/kg per day) for 21 days, animals were given a 7-day drug-free period and then challenged with an acute dose of 10 mg/kg fluoxetine. These treatment regimens resulted in a significantly increased afterdischarge threshold of HIP seizures in response to acute fluoxetine administration. The inhibitory effect of fluoxetine, however, was not present 4 weeks after long-term treatment with either fluoxetine or gepirone. The present results indicate that long-term treatment with these compounds enhances the antiepileptic effect of subsequent fluoxetine administration on the generation of HIP seizures. This effect is possibly related to the well-demonstrated evidence that fluoxetine and gepirone, on long-term treatment, facilitate net 5-HT neurotransmission through desensitization of presynaptic 5-HT autoreceptors.
Behav Brain Res. 2005 Mar 7;158(1):123-32.
Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania.
Arban R, Maraia G, Brackenborough K, Winyard L, Wilson A, Gerrard P, Large C.
Bipolar disorder is a psychiatric condition characterised by episodes of mania, depression, and underlying mood instability. Anticonvulsant drugs have an established place in the treatment of the disorder, but identifying novel drugs in this class is complicated by the absence of validated animal models. We have evaluated the efficacy of three anticonvulsant mood stabilising drugs (lamotrigine, valproate, and carbamazepine) in a model of mania, in which hyperactivity is induced by the combination of D-amphetamine and chlordiazepoxide. All three drugs were effective at preventing the hyperactivity. Lower doses of valproate and carbamazepine were required to prevent hyperactivity compared to doses required to block tonic-clonic seizures induced by pentylenetetrazole. Lamotrigine was equipotent in the two models. However, the complex pharmacology of the D-amphetamine/chlordiazepoxide model means that there may be several mechanisms by which hyperactivity can be reduced, and these may have more or less relevance to the treatment of bipolar disorder. To address this issue, we also evaluated effects of the three anticonvulsants on baseline locomotion, on activity in the presence of chlordiazepoxide alone, or on activity induced by D-amphetamine alone. Based on the results, we propose that hyperactivity induced by D-amphetamine/chlordiazepoxide may arise through dopaminergic drive coupled with disinhibition caused by low doses of the benzodiazepine. The efficacy of lamotrigine may then arise through a reduction in neuronal excitability or increased glutamate transmission, these latter a consequence of the disinhibition. Carbamazepine may also reduce excitability and glutamate release, but its broader pharmacology, manifested by sedation at higher doses complicates interpretation of its efficacy and reflects its poorer tolerability in the clinic. Valproate may be effective, at least in part, through an enhancement of GABAergic transmission. The predictive validity of the D-amphetamine/chlordiazepoxide model for efficacy in bipolar disorder remains to be established, and research with a wider range of clinically tested drugs is warranted to help validate the model further. In the meantime, the model may be useful for distinguishing novel anticonvulsant drugs with different mechanisms of action.
Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania.
Arban R, Maraia G, Brackenborough K, Winyard L, Wilson A, Gerrard P, Large C.
Bipolar disorder is a psychiatric condition characterised by episodes of mania, depression, and underlying mood instability. Anticonvulsant drugs have an established place in the treatment of the disorder, but identifying novel drugs in this class is complicated by the absence of validated animal models. We have evaluated the efficacy of three anticonvulsant mood stabilising drugs (lamotrigine, valproate, and carbamazepine) in a model of mania, in which hyperactivity is induced by the combination of D-amphetamine and chlordiazepoxide. All three drugs were effective at preventing the hyperactivity. Lower doses of valproate and carbamazepine were required to prevent hyperactivity compared to doses required to block tonic-clonic seizures induced by pentylenetetrazole. Lamotrigine was equipotent in the two models. However, the complex pharmacology of the D-amphetamine/chlordiazepoxide model means that there may be several mechanisms by which hyperactivity can be reduced, and these may have more or less relevance to the treatment of bipolar disorder. To address this issue, we also evaluated effects of the three anticonvulsants on baseline locomotion, on activity in the presence of chlordiazepoxide alone, or on activity induced by D-amphetamine alone. Based on the results, we propose that hyperactivity induced by D-amphetamine/chlordiazepoxide may arise through dopaminergic drive coupled with disinhibition caused by low doses of the benzodiazepine. The efficacy of lamotrigine may then arise through a reduction in neuronal excitability or increased glutamate transmission, these latter a consequence of the disinhibition. Carbamazepine may also reduce excitability and glutamate release, but its broader pharmacology, manifested by sedation at higher doses complicates interpretation of its efficacy and reflects its poorer tolerability in the clinic. Valproate may be effective, at least in part, through an enhancement of GABAergic transmission. The predictive validity of the D-amphetamine/chlordiazepoxide model for efficacy in bipolar disorder remains to be established, and research with a wider range of clinically tested drugs is warranted to help validate the model further. In the meantime, the model may be useful for distinguishing novel anticonvulsant drugs with different mechanisms of action.
Vojnosanit Pregl. 2004 Sep-Oct;61(5):485-90.
Antiepileptic, behavioral, and antidepressant effects of adjuvant lamotrigine therapy in drug-resistant epilepsy.
Martinovic Z, Buder N, Milovanovic M, Velickovic R.
AIM: To evaluate the behavioral effects of lamotrigine as add-on therapy in treatment-resistant epilepsy. METHODS: An open, prospective, long-term study of lamotrigine as adjuvant therapy was performed in 56 patients with drug-resistant epilepsy (female/male ratio 35/21, age range 16-51 years). All the patients kept seizure diaries, and electroencephalograms were recorded at baseline and during 24 months of the treatment. Quality of life questionnaire,Hamilton Hamilton
Antiepileptic, behavioral, and antidepressant effects of adjuvant lamotrigine therapy in drug-resistant epilepsy.
Martinovic Z, Buder N, Milovanovic M, Velickovic R.
AIM: To evaluate the behavioral effects of lamotrigine as add-on therapy in treatment-resistant epilepsy. METHODS: An open, prospective, long-term study of lamotrigine as adjuvant therapy was performed in 56 patients with drug-resistant epilepsy (female/male ratio 35/21, age range 16-51 years). All the patients kept seizure diaries, and electroencephalograms were recorded at baseline and during 24 months of the treatment. Quality of life questionnaire,
Epilepsy Behav. 2004 Oct;5(5):702-7.
Improved mood states with lamotrigine in patients with epilepsy.
Cramer JA, Hammer AE, Kustra RP.
Lamotrigine (LTG) was added to other antiepileptic drugs (AEDs) in a study of adjunctive therapy. In addition to seizure control and adverse effects, patients were evaluated for changes in mood states and quality of life. The Profile of Mood States (POMS) and 31-item Quality of Life in Epilepsy (QOLIE-31) instruments were administered at baseline (N=196), after addition of LTG as adjunctive treatment (N=155), and after withdrawal of other drugs to LTG monotherapy (N=51). POMS scores correlated highly with the QOLIE-31 Emotional Well-Being subscale, a known measure of mood. All POMS subscales were significantly improved (all P<0.0001) at the end of the adjunctive therapy phase. POMS scores remained significantly better than baseline among patients completing the conversion to monotherapy (all P<0.003). Minimal clinically important changes were determined for POMS scores. These data indicate that LTG improves mood states to a clinically important degree, even in the presence of other AEDs. The improvement likely was not a synergy but attributable only to LTG because it remained stable after withdrawal of the other AEDs.
Improved mood states with lamotrigine in patients with epilepsy.
Cramer JA, Hammer AE, Kustra RP.
Lamotrigine (LTG) was added to other antiepileptic drugs (AEDs) in a study of adjunctive therapy. In addition to seizure control and adverse effects, patients were evaluated for changes in mood states and quality of life. The Profile of Mood States (POMS) and 31-item Quality of Life in Epilepsy (QOLIE-31) instruments were administered at baseline (N=196), after addition of LTG as adjunctive treatment (N=155), and after withdrawal of other drugs to LTG monotherapy (N=51). POMS scores correlated highly with the QOLIE-31 Emotional Well-Being subscale, a known measure of mood. All POMS subscales were significantly improved (all P<0.0001) at the end of the adjunctive therapy phase. POMS scores remained significantly better than baseline among patients completing the conversion to monotherapy (all P<0.003). Minimal clinically important changes were determined for POMS scores. These data indicate that LTG improves mood states to a clinically important degree, even in the presence of other AEDs. The improvement likely was not a synergy but attributable only to LTG because it remained stable after withdrawal of the other AEDs.
Acta Psychiatr Scand Suppl. 2005;(426):21-8.
Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder.
Muzina DJ, Elhaj O, Gajwani P, Gao K, Calabrese JR.
OBJECTIVE: To review the clinical trials literature on the use of antiepileptic drugs (AED) as mood stabilizers and to suggest an evidence-based approach when utilizing these agents in bipolar disorder. METHOD: The literature is reviewed and subdivided into the following sections: carbamazepine and oxcarbazepine, valproate, lamotrigine, gabapentin and other AED, and discussion. RESULTS: Data exist to support the use of carbamazepine and valproate - and to a lesser extent, oxcarbazepine - in the management of acute manic episodes associated with bipolar I disorder. Lamotrigine, gabapentin, and other AED have not demonstrated consistent anti-manic effects. Clinical trials data favor lamotrigine over all other AED in the treatment of acute bipolar I depression and in rapid cycling bipolar disorder (particularly type II), although the absence of an active comparator in these lamotrigine trials must be noted. Lamotrigine, carbamazepine, and valproate all have evidence supporting their roles as potential long-term mood stabilizers to prevent bipolar relapse, with lamotrigine having a stronger effect in the prevention of depression. CONCLUSION: The AED are a heterogeneous group of medications with differential spectrum of efficacy in the treatment of bipolar disorder.
Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder.
Muzina DJ, Elhaj O, Gajwani P, Gao K, Calabrese JR.
OBJECTIVE: To review the clinical trials literature on the use of antiepileptic drugs (AED) as mood stabilizers and to suggest an evidence-based approach when utilizing these agents in bipolar disorder. METHOD: The literature is reviewed and subdivided into the following sections: carbamazepine and oxcarbazepine, valproate, lamotrigine, gabapentin and other AED, and discussion. RESULTS: Data exist to support the use of carbamazepine and valproate - and to a lesser extent, oxcarbazepine - in the management of acute manic episodes associated with bipolar I disorder. Lamotrigine, gabapentin, and other AED have not demonstrated consistent anti-manic effects. Clinical trials data favor lamotrigine over all other AED in the treatment of acute bipolar I depression and in rapid cycling bipolar disorder (particularly type II), although the absence of an active comparator in these lamotrigine trials must be noted. Lamotrigine, carbamazepine, and valproate all have evidence supporting their roles as potential long-term mood stabilizers to prevent bipolar relapse, with lamotrigine having a stronger effect in the prevention of depression. CONCLUSION: The AED are a heterogeneous group of medications with differential spectrum of efficacy in the treatment of bipolar disorder.
J Clin Psychiatry. 2003;64 Suppl 8:9-14.
Efficacy of newer anticonvulsant medications in bipolar spectrum mood disorders.
Evins AE.
BACKGROUND: More treatment options for all phases of bipolar disorder are needed. While lithium, valproate, and carbamazepine remain the standard of care for treatment of bipolar disorder, many patients do not respond adequately to these treatments. Some new antiepileptic medications such as lamotrigine, gabapentin, topiramate, oxcarbazepine, tiagabine, and zonisamide are beginning to be used to treat bipolar disorder. DATA SOURCES: Evidence for effectiveness of these novel antiepileptic drugs in treating acute mania and depression as well as in preventing the recurrence of mania and depression is reviewed. A MEDLINE search (1966-2001) was performed for clinical trials that were published in English using the keywords lamotrigine, gabapentin, topiramate, oxcarbazepine, tiagabine, and zonisamide, plus the terms bipolar disorder and mania. Evidence for effectiveness of monotherapy is presented first when it is available. Data from augmentation treatment studies and open case series in which standard ratings of symptoms were employed are presented when these are the only available data. DATA SYNTHESIS: Twenty-eight reports of the efficacy of novel antiepileptic medications in bipolar disorder are reviewed. Evidence is strongest for lamotrigine monotherapy in patients with bipolar depression, in some patients with rapid-cycling bipolar disorder, and as prophylaxis. Evidence for the efficacy of topiramate in acute and refractory mania is promising but comes predominantly from open trials. Although some very small studies have found that oxcarbazepine and zonisamide may have some effectiveness for treating mania, these data are very preliminary. Results are mixed from the 2 small open trials of tiagabine. Although gabapentin is widely used in bipolar disorder, controlled data do not support the use of gabapentin as an antimanic medication or mood stabilizer. CONCLUSION: More controlled trials are needed to assess the effectiveness of novel antiepileptic medications in bipolar disorder.
Efficacy of newer anticonvulsant medications in bipolar spectrum mood disorders.
Evins AE.
BACKGROUND: More treatment options for all phases of bipolar disorder are needed. While lithium, valproate, and carbamazepine remain the standard of care for treatment of bipolar disorder, many patients do not respond adequately to these treatments. Some new antiepileptic medications such as lamotrigine, gabapentin, topiramate, oxcarbazepine, tiagabine, and zonisamide are beginning to be used to treat bipolar disorder. DATA SOURCES: Evidence for effectiveness of these novel antiepileptic drugs in treating acute mania and depression as well as in preventing the recurrence of mania and depression is reviewed. A MEDLINE search (1966-2001) was performed for clinical trials that were published in English using the keywords lamotrigine, gabapentin, topiramate, oxcarbazepine, tiagabine, and zonisamide, plus the terms bipolar disorder and mania. Evidence for effectiveness of monotherapy is presented first when it is available. Data from augmentation treatment studies and open case series in which standard ratings of symptoms were employed are presented when these are the only available data. DATA SYNTHESIS: Twenty-eight reports of the efficacy of novel antiepileptic medications in bipolar disorder are reviewed. Evidence is strongest for lamotrigine monotherapy in patients with bipolar depression, in some patients with rapid-cycling bipolar disorder, and as prophylaxis. Evidence for the efficacy of topiramate in acute and refractory mania is promising but comes predominantly from open trials. Although some very small studies have found that oxcarbazepine and zonisamide may have some effectiveness for treating mania, these data are very preliminary. Results are mixed from the 2 small open trials of tiagabine. Although gabapentin is widely used in bipolar disorder, controlled data do not support the use of gabapentin as an antimanic medication or mood stabilizer. CONCLUSION: More controlled trials are needed to assess the effectiveness of novel antiepileptic medications in bipolar disorder.
Expert Opin Pharmacother. 2001 Oct;2(10):1597-608.
Anticonvulsants in the treatment of mood disorders: assessing current and future roles.
Gilmer WS.
Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.
Anticonvulsants in the treatment of mood disorders: assessing current and future roles.
Gilmer WS.
Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.
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.
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.
Antiepileptic drugs in psychiatry-focus on randomized controlled trial.
Muzina DJ, El-Sayegh S, Calabrese JR.
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.
Am J Health Syst Pharm. 1999 Oct 1;56(19):1939-44.
Gabapentin and lamotrigine in bipolar disorder.
Botts SR, Raskind J.
The utility of gabapentin and lamotrigine for the treatment of bipolar disorder is reviewed. Bipolar disorder is characterized by extreme mood fluctuations, including mania, hypomania, depression, and mixed episodes. Extrapolation of postulated mechanisms of anticonvulsant activity in bipolar disorder has led to the use of the newer anticonvulsants gabapentin and lamotrigine for therapy. Both agents appear promising on the basis of limited (often anecdotal) evidence. They may prove effective in patients with difficult cases of bipolar disorder, such as patients with rapid cycling, mixed episodes, and illness refractory to other treatments. Lamotrigine may offer a much-needed treatment alternative for bipolar depression and could be found effective for acute mania, but the need for slow dosage adjustment and the risk of rash may limit overall clinical utility. Gabapentin may offer significant advantages for acute mania: The dosage can be adjusted rapidly, adverse effects are generally minimal, the therapeutic index is high, there is no required laboratory monitoring, and there is minimal potential for interactions with other psychotropics. Until the results of randomized controlled trials are known, however, these two agents should be reserved for patients with bipolar disorder unresponsive to traditional therapies and for patients who cannot tolerate traditional agents. Preliminary evidence indicates that gabapentin and lamotrigine may be useful for the treatment of bipolar disorder.
Gabapentin and lamotrigine in bipolar disorder.
Botts SR, Raskind J.
The utility of gabapentin and lamotrigine for the treatment of bipolar disorder is reviewed. Bipolar disorder is characterized by extreme mood fluctuations, including mania, hypomania, depression, and mixed episodes. Extrapolation of postulated mechanisms of anticonvulsant activity in bipolar disorder has led to the use of the newer anticonvulsants gabapentin and lamotrigine for therapy. Both agents appear promising on the basis of limited (often anecdotal) evidence. They may prove effective in patients with difficult cases of bipolar disorder, such as patients with rapid cycling, mixed episodes, and illness refractory to other treatments. Lamotrigine may offer a much-needed treatment alternative for bipolar depression and could be found effective for acute mania, but the need for slow dosage adjustment and the risk of rash may limit overall clinical utility. Gabapentin may offer significant advantages for acute mania: The dosage can be adjusted rapidly, adverse effects are generally minimal, the therapeutic index is high, there is no required laboratory monitoring, and there is minimal potential for interactions with other psychotropics. Until the results of randomized controlled trials are known, however, these two agents should be reserved for patients with bipolar disorder unresponsive to traditional therapies and for patients who cannot tolerate traditional agents. Preliminary evidence indicates that gabapentin and lamotrigine may be useful for the treatment of bipolar disorder.
Epileptic Disord. 2004 Jun;6(2):57-75
Antiepileptic drugs: indications other than epilepsy.
Spina E, Perugi G.
Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment. Copyright John Libbey Eurotext 2003.
Antiepileptic drugs: indications other than epilepsy.
Spina E, Perugi G.
Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment. Copyright John Libbey Eurotext 2003.
J Affect Disord. 1998 Sep;50(2-3):245-51.
Use of topiramate, a new anti-epileptic as a mood stabilizer.
Marcotte D.
RATIONALE: Because some anti-epileptic drugs (AEDs) are effective in bipolar affective disorders, the new AED topiramate (TPM) may be effective in psychiatric illnesses. TPM was evaluated in mood disorders refractory to previous therapies including newer AEDs. METHODS: Charts of 58 consecutive patients, 39 outpatients (15 males, 24 females) and 19 inpatients (6 males, 13 females) were reviewed. TPM 25 mg. b.i.d. was added to existing therapy and titrated in 50 mg increments every 3-7 days. Improvement was rated on a Likert global assessment scale of marked, moderate, mild, or no improvement or worse, based on quality of sleep, appetite, mood, and concentration. RESULTS: Of the 58 patients with psychiatric disorders, 44 patients had rapid cycling bipolar disorders characterized by manic, hypomanic, or mixed episodes. Eighteen patients had previously failed to respond to lamotrigine and/or gabapentin in addition to conventional mood stabilizers. Fourteen were Bipolar I, six Bipolar II, and seven mixed, ten patients had cyclothymic disorder, seven had bipolar disorder not otherwise specified. Of the remaining 14 patients, nine had schizoaffective disorder, three patients had dementia and two had psychosis. Mean duration of TPM treatment was 16.0 weeks; mean TPM dosage approximately 200 mg/day. Thirty-six of 58 (62%) patients exhibited marked or moderate improvement, usually within days or weeks. Twenty-three of 44 (52%) patients with bipolar affective disorders showed marked or moderate improvement. Minimal/no improvement was observed in 16; six were rated as worse. Adverse events included delirium in one patient with Bipolar Disorder Type I who overmedicated with TPM (800 mg) and tranylcypromine sulfate (170 mg) combined with alcohol. Other adverse effects were minor and included: paresthesias, somnolence, fatigue, impaired concentration and memory, nausea, and diarrhoea. LIMITATIONS: This study was performed in a nonrandom open and retrospective fashion. Therefore, any findings are limited by the design of this study. CONCLUSION: TPM may be useful in patients with mood disorders unresponsive to traditional therapy and warrants further clinical investigation.
Use of topiramate, a new anti-epileptic as a mood stabilizer.
Marcotte D.
RATIONALE: Because some anti-epileptic drugs (AEDs) are effective in bipolar affective disorders, the new AED topiramate (TPM) may be effective in psychiatric illnesses. TPM was evaluated in mood disorders refractory to previous therapies including newer AEDs. METHODS: Charts of 58 consecutive patients, 39 outpatients (15 males, 24 females) and 19 inpatients (6 males, 13 females) were reviewed. TPM 25 mg. b.i.d. was added to existing therapy and titrated in 50 mg increments every 3-7 days. Improvement was rated on a Likert global assessment scale of marked, moderate, mild, or no improvement or worse, based on quality of sleep, appetite, mood, and concentration. RESULTS: Of the 58 patients with psychiatric disorders, 44 patients had rapid cycling bipolar disorders characterized by manic, hypomanic, or mixed episodes. Eighteen patients had previously failed to respond to lamotrigine and/or gabapentin in addition to conventional mood stabilizers. Fourteen were Bipolar I, six Bipolar II, and seven mixed, ten patients had cyclothymic disorder, seven had bipolar disorder not otherwise specified. Of the remaining 14 patients, nine had schizoaffective disorder, three patients had dementia and two had psychosis. Mean duration of TPM treatment was 16.0 weeks; mean TPM dosage approximately 200 mg/day. Thirty-six of 58 (62%) patients exhibited marked or moderate improvement, usually within days or weeks. Twenty-three of 44 (52%) patients with bipolar affective disorders showed marked or moderate improvement. Minimal/no improvement was observed in 16; six were rated as worse. Adverse events included delirium in one patient with Bipolar Disorder Type I who overmedicated with TPM (800 mg) and tranylcypromine sulfate (170 mg) combined with alcohol. Other adverse effects were minor and included: paresthesias, somnolence, fatigue, impaired concentration and memory, nausea, and diarrhoea. LIMITATIONS: This study was performed in a nonrandom open and retrospective fashion. Therefore, any findings are limited by the design of this study. CONCLUSION: TPM may be useful in patients with mood disorders unresponsive to traditional therapy and warrants further clinical investigation.
Eur J Pharmacol. 2003 Nov 14;481(1):67-74.
Anxiolytic effects of the novel anti-epileptic drug levetiracetam in the elevated plus-maze test in the rat.
Gower AJ, Falter U, Lamberty Y.
There is clinical evidence of anxiolytic action of several anti-epileptic drugs. We evaluated the effects of levetiracetam (Keppra), a new generation anti-epileptic drug, in the plus-maze animal test for anxiolytic activity. Levetiracetam at 17 and 54 mg/kg intraperitoneally (i.p.) was without effect when tested in naive rats. A modified version of the test was subsequently used in which open-arm exploration was decreased by exposure of the rats to a four-open-arm maze 24 h prior to drug treatment and testing. Under these conditions of enhanced anxiety, levetiracetam, 5.4 to 54 mg/kg, dose-dependently increased open-arm exploration. Chlordiazepoxide 5 mg/kg had similar effects although buspirone 0.1 to 1.0 mg/kg was inactive. The results with levetiracetam substantiate similar findings of its anxiolytic actions against chlordiazepoxide withdrawal-induced anxiety in mice and in a modified Vogel test in rats and support a potential clinical use of this drug in anxiety states.
Anxiolytic effects of the novel anti-epileptic drug levetiracetam in the elevated plus-maze test in the rat.
Gower AJ, Falter U, Lamberty Y.
There is clinical evidence of anxiolytic action of several anti-epileptic drugs. We evaluated the effects of levetiracetam (Keppra), a new generation anti-epileptic drug, in the plus-maze animal test for anxiolytic activity. Levetiracetam at 17 and 54 mg/kg intraperitoneally (i.p.) was without effect when tested in naive rats. A modified version of the test was subsequently used in which open-arm exploration was decreased by exposure of the rats to a four-open-arm maze 24 h prior to drug treatment and testing. Under these conditions of enhanced anxiety, levetiracetam, 5.4 to 54 mg/kg, dose-dependently increased open-arm exploration. Chlordiazepoxide 5 mg/kg had similar effects although buspirone 0.1 to 1.0 mg/kg was inactive. The results with levetiracetam substantiate similar findings of its anxiolytic actions against chlordiazepoxide withdrawal-induced anxiety in mice and in a modified Vogel test in rats and support a potential clinical use of this drug in anxiety states.
Epileptic Disord. 2004 Jun;6(2):57-75.
Antiepileptic drugs: indications other than epilepsy.
Spina E, Perugi G.
Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment. Copyright John Libbey Eurotext 2003.
Antiepileptic drugs: indications other than epilepsy.
Spina E, Perugi G.
Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment. Copyright John Libbey Eurotext 2003.
Contradictions on the Uses of Anti-Epileptic Drugs:
J Manag Care Pharm. 2003 Nov-Dec;9(6):559-68.
Examination of the evidence for off-label use of gabapentin.
Mack A.
OBJECTIVES: (1) Describe the relevance of off-label use of gabapentin to managed care pharmacy; (2) summarize recent FDA warnings and media reports related to off-label gabapentin use; (3) review medical information pertaining to the off-label use of gabapentin; (4) outline alternatives to off-label use of gabapentin in an evidence-based fashion, where literature exists to support such alternatives; and (5) encourage key clinicians and decision makers in managed care pharmacy to develop and support programs that restrict the use of gabapentin to specific evidence-based situations. SUMMARY: Gabapentin is approved by the U.S. Food and Drug Administration (FDA) for adjunctive therapy in treatment of partial seizures and postherpetic neuralgia. Various off-label (unapproved) uses have been reported, and the use of gabapentin for off-label purposes has reportedly exceeded use for FDAapproved indications. Pharmaceutical marketing practices and physician dissatisfaction with currently available pharmacological treatment options may be key factors that contribute to this prescribing trend. Recently, the media has focused on these issues, noting that many cases of reported safety and effectiveness of gabapentin for off-label use may have been fabricated. A thorough review of the medical and pharmacy literature related to off-label use of gabapentin was performed, and a summary of the literature for the following conditions is presented: bipolar disorder, peripheral neuropathy, diabetic neuropathy, complex regional pain syndrome, attention deficit disorder, restless legs syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep, migraine headaches, and alcohol withdrawal syndrome. A common theme in the medical literature for gabapentin is the prevalence of open-label studies and a lack of randomized controlled clinical trials for all but a small number of indications. CONCLUSIONS: In the majority of circumstances where it has reported potential for.off-label. use, gabapentin is not the optimal treatment. The off-label use of gabapentin for indications not approved by the FDA should be reserved for cases where there is solid research support (e.g., diabetic neuropathy and prophylaxis of frequent migraine headaches). Managed care pharmacists should develop programs to restrict the use of gabapentin to these specific evidence-based situations, and key decision makers in managed care practice should feel confident in supporting these use restrictions for gabapentin.
Examination of the evidence for off-label use of gabapentin.
Mack A.
OBJECTIVES: (1) Describe the relevance of off-label use of gabapentin to managed care pharmacy; (2) summarize recent FDA warnings and media reports related to off-label gabapentin use; (3) review medical information pertaining to the off-label use of gabapentin; (4) outline alternatives to off-label use of gabapentin in an evidence-based fashion, where literature exists to support such alternatives; and (5) encourage key clinicians and decision makers in managed care pharmacy to develop and support programs that restrict the use of gabapentin to specific evidence-based situations. SUMMARY: Gabapentin is approved by the U.S. Food and Drug Administration (FDA) for adjunctive therapy in treatment of partial seizures and postherpetic neuralgia. Various off-label (unapproved) uses have been reported, and the use of gabapentin for off-label purposes has reportedly exceeded use for FDAapproved indications. Pharmaceutical marketing practices and physician dissatisfaction with currently available pharmacological treatment options may be key factors that contribute to this prescribing trend. Recently, the media has focused on these issues, noting that many cases of reported safety and effectiveness of gabapentin for off-label use may have been fabricated. A thorough review of the medical and pharmacy literature related to off-label use of gabapentin was performed, and a summary of the literature for the following conditions is presented: bipolar disorder, peripheral neuropathy, diabetic neuropathy, complex regional pain syndrome, attention deficit disorder, restless legs syndrome, trigeminal neuralgia, periodic limb movement disorder of sleep, migraine headaches, and alcohol withdrawal syndrome. A common theme in the medical literature for gabapentin is the prevalence of open-label studies and a lack of randomized controlled clinical trials for all but a small number of indications. CONCLUSIONS: In the majority of circumstances where it has reported potential for.off-label. use, gabapentin is not the optimal treatment. The off-label use of gabapentin for indications not approved by the FDA should be reserved for cases where there is solid research support (e.g., diabetic neuropathy and prophylaxis of frequent migraine headaches). Managed care pharmacists should develop programs to restrict the use of gabapentin to these specific evidence-based situations, and key decision makers in managed care practice should feel confident in supporting these use restrictions for gabapentin.
Dev Med Child Neurol. 2002 Oct;17(5):647-58.
Behavioural effects of anti-epileptic drugs.
Stores G.
There is increasing evidence that various types of behavioural disturbance, other than those described for phenytoin, for example, may occur from the use of anti-epileptic medication, and it has been suggested that these disturbances may not always be reversible. There are suspicions also that certain groups of patients--especially those with structural brain damage--are particularly susceptible. These and other factors relevant to the study of the effects of anti-epileptic drugs on behaviour are comprehensively reviewed. It is concluded that the psycho-pharmacology of anti-epileptic drugs is unsatisfactory at present because of inadequate and unsophisticated reporting of behavioural change and because of the common problem of polypharmacy, and that more accurate observations are needed on less heterogeneous groups of patients that have been described in the past.
Behavioural effects of anti-epileptic drugs.
Stores G.
There is increasing evidence that various types of behavioural disturbance, other than those described for phenytoin, for example, may occur from the use of anti-epileptic medication, and it has been suggested that these disturbances may not always be reversible. There are suspicions also that certain groups of patients--especially those with structural brain damage--are particularly susceptible. These and other factors relevant to the study of the effects of anti-epileptic drugs on behaviour are comprehensively reviewed. It is concluded that the psycho-pharmacology of anti-epileptic drugs is unsatisfactory at present because of inadequate and unsophisticated reporting of behavioural change and because of the common problem of polypharmacy, and that more accurate observations are needed on less heterogeneous groups of patients that have been described in the past.
J Psychiatr Res. 2005 Mar;39(2):191-6.
Investigation of the effects of tianeptine and fluoxetine on pentylenetetrazole-induced seizures in rats.
Ceyhan M, Kayir H, Uzbay IT.
The effects of tianeptine and fluoxetine on pentylenetetrazole (PTZ)-induced seizures in rats were investigated. Female Wistar rats (172-278 g) were used in the study. Tianeptine (1.25, 2.5, 5, 10 and 20 mg/kg) and fluoxetine (2.5, 5, 10 and 20 mg/kg) or saline were injected to rats intraperitoneally 30 min before PTZ (50 mg/kg) injections. Immediately after PTZ administrations, latency and intensity of the PTZ-induced seizures was recorded and scored, respectively. Fluoxetine (2.5-20 mg/kg) did not produce any significant difference in latency and intensity of the PTZ-induced seizures. Although tianeptine (1.25-20 mg/kg) also did not affect the latency time, it produced significant attenuations in the intensity of the seizures. Tianeptine did not cause any significant change in the locomotor activity of the rats. The results of this preliminary study suggest that tianeptine but not fluoxetine has some inhibitory effects on PTZ-induced seizures in rats.
Investigation of the effects of tianeptine and fluoxetine on pentylenetetrazole-induced seizures in rats.
Ceyhan M, Kayir H, Uzbay IT.
The effects of tianeptine and fluoxetine on pentylenetetrazole (PTZ)-induced seizures in rats were investigated. Female Wistar rats (172-278 g) were used in the study. Tianeptine (1.25, 2.5, 5, 10 and 20 mg/kg) and fluoxetine (2.5, 5, 10 and 20 mg/kg) or saline were injected to rats intraperitoneally 30 min before PTZ (50 mg/kg) injections. Immediately after PTZ administrations, latency and intensity of the PTZ-induced seizures was recorded and scored, respectively. Fluoxetine (2.5-20 mg/kg) did not produce any significant difference in latency and intensity of the PTZ-induced seizures. Although tianeptine (1.25-20 mg/kg) also did not affect the latency time, it produced significant attenuations in the intensity of the seizures. Tianeptine did not cause any significant change in the locomotor activity of the rats. The results of this preliminary study suggest that tianeptine but not fluoxetine has some inhibitory effects on PTZ-induced seizures in rats.
Neurosci Lett. 2005 Jan 20;373(3):226-31. Epub 2004 Oct 30.
The effect of fluoxetine in a model of chemically induced seizures--behavioral and immunocytochemical study.
Zienowicz M, Wislowska A, Lehner M, Taracha E, Skorzewska A, Maciejak P, Plaznik A.
The aim of this study was to examine the effects of acute fluoxetine treatment on pentylenetetrazol-induced convulsions in order to shape a model of seizures associated with treatment with antidepressants in rats. Moreover, the putative role of the hippocampal formation in this respect was investigated with the help of c-fos immuncytochemistry to mark local neuronal activity. It was found that fluoxetine (10.0 mg/kg, i.p.) enhanced the proconvulsive effect of pentylenetetrazol (50.0 mg/kg, i.p.), and simultaneously inhibited pentylenetetrazol-stimulated c-Fos expression in some areas of the hippocampus. Fluoxetine pretreatment did not alter pentylenetetrazol brain concentration indicating that this phenomenon was not related to the pharmacokinetic interaction. It is suggested that inhibition by fluoxetine of some neuronal populations contributing to the local feedback mechanism controlling excessive epileptiform discharges within the hippocampus might lead to an increase in epileptic activity. The reported in the present paper fluoxetine versus pentylenetetrazol interaction may, therefore, serve as a model of seizures associated with treatment with antidepressants.
The effect of fluoxetine in a model of chemically induced seizures--behavioral and immunocytochemical study.
Zienowicz M, Wislowska A, Lehner M, Taracha E, Skorzewska A, Maciejak P, Plaznik A.
The aim of this study was to examine the effects of acute fluoxetine treatment on pentylenetetrazol-induced convulsions in order to shape a model of seizures associated with treatment with antidepressants in rats. Moreover, the putative role of the hippocampal formation in this respect was investigated with the help of c-fos immuncytochemistry to mark local neuronal activity. It was found that fluoxetine (10.0 mg/kg, i.p.) enhanced the proconvulsive effect of pentylenetetrazol (50.0 mg/kg, i.p.), and simultaneously inhibited pentylenetetrazol-stimulated c-Fos expression in some areas of the hippocampus. Fluoxetine pretreatment did not alter pentylenetetrazol brain concentration indicating that this phenomenon was not related to the pharmacokinetic interaction. It is suggested that inhibition by fluoxetine of some neuronal populations contributing to the local feedback mechanism controlling excessive epileptiform discharges within the hippocampus might lead to an increase in epileptic activity. The reported in the present paper fluoxetine versus pentylenetetrazol interaction may, therefore, serve as a model of seizures associated with treatment with antidepressants.
Expert Opin Pharmacother. 2002 Jan;3(1):59-71.
Oxcarbazepine.
Beydoun A, Kutluay E.
Oxcarbazepine is one of the recently introduced anti-epileptic drugs (AEDs) in theUS
Oxcarbazepine.
Beydoun A, Kutluay E.
Oxcarbazepine is one of the recently introduced anti-epileptic drugs (AEDs) in the
Epilepsy Res. 2005 Jan;63(1):17-25. Epub 2004 Dec 8.
Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents.
Danielsson BR, Lansdell K, Patmore L, Tomson T.
Drugs that inhibit the cardiac rapid delayed rectifier potassium ion current (I(Kr)) can be proarrhythmic and their clinical use has been associated with sudden unexpected death (SUD) due to cardiac arrhythmia. SUD is 20-40 times more common among people with epilepsy than in the general population and case-control studies have identified polytherapy with antiepileptic drugs (AEDs) as a risk factor. In a previous study, it was described that the old AEDs phenytoin and phenobarbital had the potential to inhibit the I(Kr) channel and it was suggested that this could contribute to the increased risk for SUD in patients with epilepsy. In this study, we have investigated the I(Kr) blocking potential of some more recently introduced AEDs, lamotrigine (LTG), topiramate (TPM) and gapapentin (GBP). The whole cell patch-clamp recording technique was used to study the effects on I(Kr) channels expressed by the human ether-a-go-go related gene (hERG) stably expressed in human embryo kidney (HEK) 293 cells. Tail currents, which are purely related to hERG currents, were blocked with IC50 and IC20 (the concentrations when 50% and 20% inhibition was obtained compared to control values) of 229 and 21 microM, respectively, for LTG. A 40% inhibition of tail currents was obtained at GBP concentrations of 100 mM and a 20% inhibition at 54 mM. A 35% inhibition of tail currents was obtained at TPM concentrations of 1000 microM and a 20% inhibition at 87 microM, respectively. Collective data show that drugs with the same margins (ratio hERG IC50/unbound therapeutic concentration) as LTG, may have arrhythmogenic potential. The risk for arrhythmia may be clinically significant in the presence of predisposing factors such as seizure-induced acidosis and in the case of concurrent treatment with other I(Kr) blocking drugs, or in case of pharmacokinetic drug-drug interactions resulting in excessively high concentrations of LTG.
Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents.
Danielsson BR, Lansdell K, Patmore L, Tomson T.
Drugs that inhibit the cardiac rapid delayed rectifier potassium ion current (I(Kr)) can be proarrhythmic and their clinical use has been associated with sudden unexpected death (SUD) due to cardiac arrhythmia. SUD is 20-40 times more common among people with epilepsy than in the general population and case-control studies have identified polytherapy with antiepileptic drugs (AEDs) as a risk factor. In a previous study, it was described that the old AEDs phenytoin and phenobarbital had the potential to inhibit the I(Kr) channel and it was suggested that this could contribute to the increased risk for SUD in patients with epilepsy. In this study, we have investigated the I(Kr) blocking potential of some more recently introduced AEDs, lamotrigine (LTG), topiramate (TPM) and gapapentin (GBP). The whole cell patch-clamp recording technique was used to study the effects on I(Kr) channels expressed by the human ether-a-go-go related gene (hERG) stably expressed in human embryo kidney (HEK) 293 cells. Tail currents, which are purely related to hERG currents, were blocked with IC50 and IC20 (the concentrations when 50% and 20% inhibition was obtained compared to control values) of 229 and 21 microM, respectively, for LTG. A 40% inhibition of tail currents was obtained at GBP concentrations of 100 mM and a 20% inhibition at 54 mM. A 35% inhibition of tail currents was obtained at TPM concentrations of 1000 microM and a 20% inhibition at 87 microM, respectively. Collective data show that drugs with the same margins (ratio hERG IC50/unbound therapeutic concentration) as LTG, may have arrhythmogenic potential. The risk for arrhythmia may be clinically significant in the presence of predisposing factors such as seizure-induced acidosis and in the case of concurrent treatment with other I(Kr) blocking drugs, or in case of pharmacokinetic drug-drug interactions resulting in excessively high concentrations of LTG.
Other Uses for Anti-Epileptic Drugs:
Am J Geriatr Pharmacother. 2003 Sep;1(1):18-37.
Oxcarbazepine, topiramate, zonisamide, and levetiracetam: potential use in neuropathic pain.
Guay DR
Oxcarbazepine, topiramate, zonisamide, and levetiracetam: potential use in neuropathic pain.
BACKGROUND: Oxcarbazepine, topiramate, zonisamide, and levetiracetam are the antiepileptic drugs (AEDs) most recently approved by the US Food and Drug Administration. Based on the experience with carbamazepine, gabapentin, and lamotrigine, these newer AEDs are being investigated for the management of neuropathic pain. OBJECTIVE: This article reviews preclinical and clinical data on the efficacy and tolerability of these 4 AEDs in the management of neuropathic pain, as well as the pharmacokinetics, drug-interaction potential, adverse effects, and dosing of these agents, with an emphasis on their use in older individuals. METHODS: Relevant studies were identified through a MEDLINE search of the Englidh-language literature published between 1986 and May 2003, a review of the reference lists of identified articles, and abstracts from the annual meetings of the American Academy
Basic Clin Pharmacol Toxicol. 2005 Jun;96(6):399-409.
Antidepressants in the treatment of neuropathic pain.
Sindrup SH, Otto M, Finnerup NB, Jensen TS.
Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2-3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class - may among the antidepressants - favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain.
Antidepressants in the treatment of neuropathic pain.
Sindrup SH, Otto M, Finnerup NB, Jensen TS.
Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2-3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class - may among the antidepressants - favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain.
Ann Acad Med Singapore
Facial pain: trigeminal neuralgia.
Lee KH.
Atypical facial pain is a loose term used to encompass a wide range of facial pain syndromes including those of dental and ear, nose and throat (ENT) aetiology. Often, it is associated with psychiatric conditions like depression and psychosomatic illnesses. This facial pain typically does not follow anatomical boundaries or its explainable by present day neurophysiological understanding. The pain is often constant with no remission and is aggravated by stress. Treatment is difficult and often directed to the psychiatric cause. Surgical treatment is contraindicated. Trigeminal neuralgia on the other hand, can be effectively treated. Pain in the trigeminal distribution is paroxysmal, precipitated by trigger factors and there is no pain in between attacks. The aetiology of trigeminal neuralgia is still unknown though current thinking is that there is a peripheral disturbance or damage with cerebral brainstem disinhibition of the trigeminal apparatus. This results in a paroxysmal discharge and reverberation of pain impulses when a trigger point is elicited. Therefore, anti-epileptic drugs like tegretol can be effective in controlling trigeminal neuralgia in the majority of patients, at least in the initial stages. For unknown reasons however, medical treatment either is not effective at all from the very beginning or fails after a few years. Surgery then becomes the only available therapeutic option. If the peripheral disturbance is due to an organic cause like a tumour, surgical approaches should be directed towards its removal. Often the pain will also resolve. If the trigeminal neuralgia is of the idiopathic variety, then the surgeon has a choice of either peripheral percutaneous retrogasserian ganglionectomies or central approaches like microvascular decompression and trigeminal tractotomy.
Facial pain: trigeminal neuralgia.
Lee KH.
Atypical facial pain is a loose term used to encompass a wide range of facial pain syndromes including those of dental and ear, nose and throat (ENT) aetiology. Often, it is associated with psychiatric conditions like depression and psychosomatic illnesses. This facial pain typically does not follow anatomical boundaries or its explainable by present day neurophysiological understanding. The pain is often constant with no remission and is aggravated by stress. Treatment is difficult and often directed to the psychiatric cause. Surgical treatment is contraindicated. Trigeminal neuralgia on the other hand, can be effectively treated. Pain in the trigeminal distribution is paroxysmal, precipitated by trigger factors and there is no pain in between attacks. The aetiology of trigeminal neuralgia is still unknown though current thinking is that there is a peripheral disturbance or damage with cerebral brainstem disinhibition of the trigeminal apparatus. This results in a paroxysmal discharge and reverberation of pain impulses when a trigger point is elicited. Therefore, anti-epileptic drugs like tegretol can be effective in controlling trigeminal neuralgia in the majority of patients, at least in the initial stages. For unknown reasons however, medical treatment either is not effective at all from the very beginning or fails after a few years. Surgery then becomes the only available therapeutic option. If the peripheral disturbance is due to an organic cause like a tumour, surgical approaches should be directed towards its removal. Often the pain will also resolve. If the trigeminal neuralgia is of the idiopathic variety, then the surgeon has a choice of either peripheral percutaneous retrogasserian ganglionectomies or central approaches like microvascular decompression and trigeminal tractotomy.
Rinsho Shinkeigaku. 2004 Nov;44(11):818-9.
Headache originating front-orbital area
Headache originating front-orbital area
Sakuta M.
Headache originating front-orbital area can be divided to (1) Which has no autonomic symptoms such as lacrimation, rhinorrea, rhinostasis. This include psychogenic headache and epileptic headache. In the case of psychogenic headache, pericranial tenderness is not observed, and headache is medium in intensity. Most often patient complains of a headache originating frontal area. There are more than five various symptoms such as general malaise, numbness, tingling sensation, vertigo, sleeplessness. However, although symptoms are multiple, patients spend a life commonly. In other words, a patient is protected by a headache against his or her stress. No medication is needed in such a case. In epileptic headache, pressing type pain is felt over the forehead for several minutes to a few hours. Tremor or convulsion sometimes follow the headache. EEG shows spike and wave activities. In the case of focal epilepsy, headache occurs contralateral to the focus. Anti-epileptic drugs such as VPA or CBZ is a choice in such case, and headache as well as seizure disappears. (2) Front-orbital headache with autonomic symptoms include various trigeminal autonomic cephalalgias. These include cluster headache, episodic paroxysmal hemicrania, hemicrania continua, among others. Precise history taking is necessary for the treatment, because no drug is 100% effective.
Headache originating front-orbital area can be divided to (1) Which has no autonomic symptoms such as lacrimation, rhinorrea, rhinostasis. This include psychogenic headache and epileptic headache. In the case of psychogenic headache, pericranial tenderness is not observed, and headache is medium in intensity. Most often patient complains of a headache originating frontal area. There are more than five various symptoms such as general malaise, numbness, tingling sensation, vertigo, sleeplessness. However, although symptoms are multiple, patients spend a life commonly. In other words, a patient is protected by a headache against his or her stress. No medication is needed in such a case. In epileptic headache, pressing type pain is felt over the forehead for several minutes to a few hours. Tremor or convulsion sometimes follow the headache. EEG shows spike and wave activities. In the case of focal epilepsy, headache occurs contralateral to the focus. Anti-epileptic drugs such as VPA or CBZ is a choice in such case, and headache as well as seizure disappears. (2) Front-orbital headache with autonomic symptoms include various trigeminal autonomic cephalalgias. These include cluster headache, episodic paroxysmal hemicrania, hemicrania continua, among others. Precise history taking is necessary for the treatment, because no drug is 100% effective.
Pain. 2003 Sep;105(1-2):355-62.
Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig.
Fox A, Gentry C, Patel S, Kesingland A, Bevan S.
Anti-epileptic drugs (AEDs) are increasingly used for the treatment of neuropathic pain. Oxcarbazepine is a recently introduced AED that is effective in treating epilepsy and has an improved side-effect profile compared to existing therapies. Here we have examined the effect of oxcarbazepine and other AEDs in a model of neuropathic pain in the rat and guinea-pig. Oxcarbazepine and carbamazepine (3-100 mg x kg(-1)) did not affect mechanical hyperalgesia or tactile allodynia induced by partial sciatic nerve ligation in the rat following oral administration. However, in the same model in the guinea-pig, both drugs produced up to 90% reversal of mechanical hyperalgesia with respective D(50) values of 10.7 and 0.8 mg x kg(-1). The active human metabolite of oxcarbazepine, monohydroxy derivative, was similarly active against mechanical hyperalgesia in the guinea-pig but not the rat. Lamotrigine (3-100 mg x kg(-1), p.o.) was effective against mechanical hyperlagesia in both species although it showed greater efficacy and potency in the guinea-pig (D(50) 4.7 mg x kg(-1)) compared to the rat (D(50) 27 mg kg(-1)). Lamotrigine produced slight inhibition of tactile allodynia in the rat only at the highest dose tested of 100 mg x kg(-1). Gabapentin was poorly active against mechanical hyperalgesia in both the rat and guinea-pig following a single oral administration (100 mg x kg(-1)), although upon repeated administration it produced up to 70 and 90% reversal in rat and guinea-pig, respectively. Gabapentin did however produce significant dose-related reversal of tactile allodynia in the rat following a single administration. These data show that oxcarbazepine and other AEDs are effective anti-hyperalgesic or anti-allodynic agents in an animal model of neuropathic pain, and provide further support for their use in the treatment of neuropathic pain in the clinic.
Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig.
Fox A, Gentry C, Patel S, Kesingland A, Bevan S.
Anti-epileptic drugs (AEDs) are increasingly used for the treatment of neuropathic pain. Oxcarbazepine is a recently introduced AED that is effective in treating epilepsy and has an improved side-effect profile compared to existing therapies. Here we have examined the effect of oxcarbazepine and other AEDs in a model of neuropathic pain in the rat and guinea-pig. Oxcarbazepine and carbamazepine (3-100 mg x kg(-1)) did not affect mechanical hyperalgesia or tactile allodynia induced by partial sciatic nerve ligation in the rat following oral administration. However, in the same model in the guinea-pig, both drugs produced up to 90% reversal of mechanical hyperalgesia with respective D(50) values of 10.7 and 0.8 mg x kg(-1). The active human metabolite of oxcarbazepine, monohydroxy derivative, was similarly active against mechanical hyperalgesia in the guinea-pig but not the rat. Lamotrigine (3-100 mg x kg(-1), p.o.) was effective against mechanical hyperlagesia in both species although it showed greater efficacy and potency in the guinea-pig (D(50) 4.7 mg x kg(-1)) compared to the rat (D(50) 27 mg kg(-1)). Lamotrigine produced slight inhibition of tactile allodynia in the rat only at the highest dose tested of 100 mg x kg(-1). Gabapentin was poorly active against mechanical hyperalgesia in both the rat and guinea-pig following a single oral administration (100 mg x kg(-1)), although upon repeated administration it produced up to 70 and 90% reversal in rat and guinea-pig, respectively. Gabapentin did however produce significant dose-related reversal of tactile allodynia in the rat following a single administration. These data show that oxcarbazepine and other AEDs are effective anti-hyperalgesic or anti-allodynic agents in an animal model of neuropathic pain, and provide further support for their use in the treatment of neuropathic pain in the clinic.
Clin Ther. 2003 Oct;25(10):2506-38.
Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine.
Pappagallo M.
BACKGROUND: Both neuropathic pain and migraine are now being treated with a variety of newer antiepileptic drugs (AEDs). The proven efficacy of gabapentin in postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), and of divalproex sodium in the prevention of migraine has led to increased clinical investigation of the newer AEDs for these conditions. While basic and clinical research are expanding the knowledge base concerning the fundamental mechanisms of neuropathic pain and migraine, growing recognition of the similarities in the pathophysiology of epilepsy, migraine, and various chronic pain disorders has further heightened interest in exploring the newer AEDs in the treatment of these conditions.OBJECTIVE: The goals of this article were to review the empiric basis and scientific rationale for the use of AEDs in the treatment of neuropathic pain and migraine; summarize available clinical research on the use of 5 newer AEDs (gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide) in these conditions; and provide a summary comparison of the dosing, tolerability, and drug-interaction potential of these agents.METHODS: Relevant English-language articles were identified through searches of MEDLINE (1990-March 2003), American Academy of Neurology abstracts (1999-2003), and American Epilepsy Society abstracts (2000-2002). The search terms were antiepileptic medication or drug, migraine headache, neuropathic pain, pathophysiology, treatment, mechanism of action, gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide.CONCLUSIONS: The newer AEDs possess the potential advantages of better tolerability and fewer drug-drug interactions compared with standard treatments such as tricyclic antidepressants or established AEDs. However, with the exception of data supporting the efficacy of gabapentin in PHS and PDN, there is currently insufficient evidence to determine whether the newer AEDs have equal or superior efficacy relative to proven pharmacotherapies.
Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine.
Pappagallo M.
BACKGROUND: Both neuropathic pain and migraine are now being treated with a variety of newer antiepileptic drugs (AEDs). The proven efficacy of gabapentin in postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), and of divalproex sodium in the prevention of migraine has led to increased clinical investigation of the newer AEDs for these conditions. While basic and clinical research are expanding the knowledge base concerning the fundamental mechanisms of neuropathic pain and migraine, growing recognition of the similarities in the pathophysiology of epilepsy, migraine, and various chronic pain disorders has further heightened interest in exploring the newer AEDs in the treatment of these conditions.OBJECTIVE: The goals of this article were to review the empiric basis and scientific rationale for the use of AEDs in the treatment of neuropathic pain and migraine; summarize available clinical research on the use of 5 newer AEDs (gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide) in these conditions; and provide a summary comparison of the dosing, tolerability, and drug-interaction potential of these agents.METHODS: Relevant English-language articles were identified through searches of MEDLINE (1990-March 2003), American Academy of Neurology abstracts (1999-2003), and American Epilepsy Society abstracts (2000-2002). The search terms were antiepileptic medication or drug, migraine headache, neuropathic pain, pathophysiology, treatment, mechanism of action, gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide.CONCLUSIONS: The newer AEDs possess the potential advantages of better tolerability and fewer drug-drug interactions compared with standard treatments such as tricyclic antidepressants or established AEDs. However, with the exception of data supporting the efficacy of gabapentin in PHS and PDN, there is currently insufficient evidence to determine whether the newer AEDs have equal or superior efficacy relative to proven pharmacotherapies.
Semin Neurol. 1997;17(4):325-33.
Migraine treatment.
Young WB,Silberstein SD
Migraine is a primary headache disorder characterized by recurring attacks of pain and associated symptoms. Migraine sufferers require a continuum of clinical care that depends on their disability and response to treatment. Treatment consists of: (1) prevention of attacks by avoidance of triggers; (2) the use of nonpharmacologic treatments; (3) treatment of the acute attack; and (4) long-term prophylactic therapy. Migraine is comorbid for affective disorders, epilepsy, stroke, and mitral valve prolapse. The therapy selected depends on the headache severity and frequency, the pattern of associated symptoms, comorbid illnesses, and the patient's treatment response profile. Acute treatment can be symptomatic or specific, using drugs such as dihydroergotamine (DHE) or sumatriptan. Preventive treatment can be episodic, subacute, or chronic. The major drug groups include beta-adrenergic blockers, anti-depressants, calcium channel blockers, serotonin antagonists, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs). These can be divided into two major categories and second-line choices.
Migraine treatment.
Young WB,
Migraine is a primary headache disorder characterized by recurring attacks of pain and associated symptoms. Migraine sufferers require a continuum of clinical care that depends on their disability and response to treatment. Treatment consists of: (1) prevention of attacks by avoidance of triggers; (2) the use of nonpharmacologic treatments; (3) treatment of the acute attack; and (4) long-term prophylactic therapy. Migraine is comorbid for affective disorders, epilepsy, stroke, and mitral valve prolapse. The therapy selected depends on the headache severity and frequency, the pattern of associated symptoms, comorbid illnesses, and the patient's treatment response profile. Acute treatment can be symptomatic or specific, using drugs such as dihydroergotamine (DHE) or sumatriptan. Preventive treatment can be episodic, subacute, or chronic. The major drug groups include beta-adrenergic blockers, anti-depressants, calcium channel blockers, serotonin antagonists, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs). These can be divided into two major categories and second-line choices.
Cleve Clin J Med. 1998;65 Suppl 1:SI21-9; discussion SI45-7.
Anticonvulsants for neuropathic pain and detoxification.
Covington
It is now well demonstrated that several anticonvulsants have a role in the treatment of neuropathic pain and also in withdrawal from benzodiazepines, sedatives, and perhaps alcohol. Valproic acid, carbamazepine, gabapentin, clonazepam, and lamotrigine are appropriate treatments for neuropathic pain, effective to a degree dependent on the underlying pathophysiology. While less effective than newer agents, there are situations in which phenytoin remains useful. Currently, a limited understanding of both the processes responsible for pain and the specific effects of each agent prevents prediction of individual response to these drugs, often necessitating trials of several drugs before the best one is found. It is interesting that the anticonvulsant drugs most useful for neuropathic pain are the same ones effective in sedative withdrawal, bipolar disorder, and several anxiety disorders. Issues of neural hypersensitivity and kindling, therefore, may prove to be unifying concepts for these conditions.
Anticonvulsants for neuropathic pain and detoxification.
It is now well demonstrated that several anticonvulsants have a role in the treatment of neuropathic pain and also in withdrawal from benzodiazepines, sedatives, and perhaps alcohol. Valproic acid, carbamazepine, gabapentin, clonazepam, and lamotrigine are appropriate treatments for neuropathic pain, effective to a degree dependent on the underlying pathophysiology. While less effective than newer agents, there are situations in which phenytoin remains useful. Currently, a limited understanding of both the processes responsible for pain and the specific effects of each agent prevents prediction of individual response to these drugs, often necessitating trials of several drugs before the best one is found. It is interesting that the anticonvulsant drugs most useful for neuropathic pain are the same ones effective in sedative withdrawal, bipolar disorder, and several anxiety disorders. Issues of neural hypersensitivity and kindling, therefore, may prove to be unifying concepts for these conditions.
Conclusion:
In conclusion, there is a correlation between drugs used to treat epilepsy and patients who have psychological symptoms such as anxiety, depression and bipolar disorders which may explain why psychotropic drugs are the preferred choice of doctors for the treatment of epilepsy and vice versa. This may be caused from anatomopathologic abnormalities seen in the limbic system because of the use of antiepileptic drugs which may have negative psychotropic effects. However, the treatment for bipolar disorder without the presence of epilepsy using anti-epileptic drugs such as lamotrigine, valproate, and carbamazepine, which are known for mood stabilization showed that these drugs controlled the amount of D-amphetamine and chlordiazepoxide and therefore preventing bipolar symptoms.
Anti-epileptic drugs are used for the treatment of the following: neuropathic pain (gabapentin-neurontin),trigeminal neuralgia (carbamazepine), diabetic neuropathy, migraine pain (valproic acid in general), anti-anxiety (levetiracetam) essential tremor (primidone), manic depression (dipropylacetamide) and detoxification from benzodiazepines. This shows that there is a wide range of symptoms that can be controlled rather than with the use of narcotics. Most doctors prefer to go this route; however there is not much known about the long term effects.
Several studies have shown that there is a problem with using anti-psychotic drugs for epilepsy and anti-epileptic drugs used for psychological disorders. The reason being is the lack of research and clinical implications reported. On a lot of these drugs the FDA has not approved them for off label use. In other words, yes these drugs have been FDA approved, however, not for any other use then their original intent. In addition, the wide use of anti-epileptic drugs could have ramifications/consequences. For instance, negative behavioral effects which may not be reversible. It has also been reported that tianeptine and fluoxetine on pentyleneteranzole induced seizures, these anti-psychotic drugs when in the presence of another substance can cause more harm than good. This is the reason these particular drugs need to be carefully monitored! In addition, drugs such as phenytoin and Phenobarbital, which are older generations of drugs, however they should not be discredited. The risk for arrhythmia may be increased which could lead to death.
