Epileptic Disorders
MENUAntiepileptic drugs: indications other than epilepsy Volume 6, issue 2, June 2004
Auteur(s) : Edoardo Spina1, Giulio Perugi2
1. Section of Pharmacology, Department of Clinical and
Experimental Medicine and Pharmacology, University of Messina,
Messina
2. Department of Psychiatry, Neurobiology, Pharmacology and
Biotechnologies, Psychiatry Section, University of Pisa, Pisa,
Italy
Antiepileptic drugs (AEDs) are widely used for the treatment of
a variety of nonepileptic neurological conditions and psychiatric
disorders. This presumably reflects their complex mechanism of
action involving a wide range of pharmacological effects on
different neurotransmitter systems and ion channels. Information
from the utilization of both traditional and newer AEDs in some
clinical disorders other than epilepsy has been mostly based on
case reports, uncontrolled studies or small randomised clinical
trials and thus can not be used to determine the efficacy and
safety of these medications. In other cases, evidence for efficacy
has been supported by well designed, large, phase III trials and
some AEDs are approved for selected indications.
The present article reviews the available evidence for the
efficacy and safety of AEDs for the treatment of neurological
conditions outside epilepsy and psychiatric disorders. For each
clinical indication, an attempt has been made to identify the
rationale for using AEDs, to describe the main results of
randomized clinical trials or, if not available, of relevant
open-label studies, and to examine the role played by AEDs in the
overall treatment of that condition.
Use of antiepileptic drugs in neurological conditions other than epilepsy
Older and newer AEDs are increasingly used for the treatment of various neurological disorders other than epilepsy. Evidence from randomized clinical trials indicates that trigeminal neuralgia, neuropathic pain, migraine and essential tremor are the clinical conditions for which some AEDs may represent the treatment of choice or a valuable alternative to standard treatments [1].
Trigeminal neuralgia
Trigeminal neuralgia, also known as tic douloureux, is a paroxysmal form of facial pain usually affecting the second and third division of the trigeminal nerve. The abrupt nature of the painful attacks (with a temporal profile similar to that of seizures), led to the discovery that some anticonvulsant drugs are effective against this condition. Carbamazepine is commonly prescribed as first-line therapy for trigeminal neuralgia [2, 3]. Other traditional and newer anticonvulsants including valproic acid (sodium valproate), lamotrigine, gabapentin and topiramate have been used for the treatment of trigeminal neuralgia. With the exception of valproic acid and lamotrigine, evidence of their efficacy is based on uncontrolled studies and their use in clinical practice can not be recommended. The results of randomized clinical trials on the use of AEDs in patients with trigeminal neuralgia are illustrated in Table 1.
Table 1. Randomized clinical trials of anti-epileptics for the treatment of trigeminal neuralgia.
Study (Ref.) |
No. treated (diagnosis) | Design | Daily dosage | Duration | Main outcome |
---|---|---|---|---|---|
Carbamazepine (CBZ) | |||||
Rockliff and Davis, 1966 [6] | 9 | db, pc, co | 600 mg | three days | CBZ preferred by 8/9; CBZ and placebo equally effective in 1/9 |
Campbell et al., 1966 [7] | 77 | db, pc, co | 400-800 mg | four weeks |
Responders: CBZ 57%; placebo 15% |
Killian and Fromm, 1968 [8] |
42 (30 with trigeminal neuralgia) |
db, pc, co | 400-1 000 mg | 10 days | CBZ: mild improvement to complete recovery in all patients; placebo: minimal or no improvement in all patients |
Nicol, 1969 [9] |
64 (54 with trigeminal neuralgia) |
db, pc, pco | 100-2 400 mg | two weeks |
Responders: CBZ 15/20; placebo 6/24 |
Vilming et al., 1986 [10] | 12 | db, ac, pg | CBZ: 900 mg, tizanidine: 18 mg | three weeks |
Responders: CBZ 4/6; tizanidine 1/5 |
Lindstrom and Lindblom, 1987 [11] | 12 | db, ac, co | CBZ: max tolerated dose, Tocainide: 60 mg/kg | two weeks | CBZ and tocainide equally effective (12/12) |
Leichin et al., 1989 [12] | 48 | db, ac, co |
CBZ: 300-1 200 mg, pimozide: 4-12 mg |
eight weeks | Responders: CBZ 27/48; pimozide 18/48 |
Valproic acid (VPA) | |||||
Desai et al., 1991 [16] | 40 | db, pc, pg |
VPA: 800-1 600 mg, CBZ: 600-900 mg, Baclofen: 25-75 mg |
10 days |
Responders: VPA + CBZ + baclofen 10/10; VPA
8/10; CBZ 2/10; baclofen 7/10 |
Lamotrigine (LTG) | |||||
Zakrzewska et al., 1997 [17] | 14 | db, pc, co, ao | 400 mg | 31 days |
Responders: LTG 11/13; placebo 2/14 |
Carbamazepine
Carbamazepine can be considered the drug of choice for the
treatment of trigeminal neuralgia [2, 3]. Its effect on pain
suppression probably occurs via central and peripheral mechanisms.
Carbamazepine exerts a use-dependent inhibition of sodium channels
and reduces the frequency of sustained repetitive firing of action
potential in neurons [4].
The experience with carbamazepine dates back to 1962 when Bloom
first described its analgesic effect in patients with trigeminal
neuralgia [5]. Since then several randomized clinical trials,
reviewed by Beghi [4], have documented the effectiveness of
carbamazepine [6-12]. In these trials, carbamazepine, used at a
daily dose ranging from 100 to 2 400 mg, was manifestly
superior to placebo [6-9] and more effective or better tolerated
than other active comparators such as tizanidine [10], tocainide
[11] and pimozide [12].
Carbamazepine effectively relieves the pain of trigeminal
neuralgia in 70 to 80% of patients initially. Effective pain relief
continues in approximately 50% of cases after prolonged
administration. In order to avoid initial toxicity, the starting
dose may be 100-200 mg/day. The daily dose should be then
increased gradually until pain relief or adverse effects occur, up
to 1 000-1 200 mg. Due to the spontaneous remission
of pain and the toxic effects during chronic treatment with
carbamazepine, drug discontinuation is recommended after two-three
months in patients with pain relief. In patients not responding to
carbamazepine, other anticonvulsants such as phenytoin, gabapentin,
lamotrigine or topiramate could be attempted as monotherapy or in
combination. In a controlled study of patients with trigeminal
neuralgia, optimal pain control was documented at the concentration
range of 5.7 to 10.1 µg/mL [13]. The metabolite of
carbamazepine, carbamazepine-10,11-epoxide, has antineuralgic
efficacy comparable to the parent compound [14].
Phenytoin
Evidence for the efficacy of phenytoin in trigeminal neuralgia is based only on uncontrolled studies [2]. Pain relief is obtained in approximately 60% of patients initially. As tachyphylaxis may develop within a short time, only about 20-30% of patients will experience sustained pain relief. Phenytoin should be used at dosages ranging from 300 to 600 mg/day. The greatest practical value of phenytoin lies in the management of patients presenting with acute neuralgic crisis. Since phenytoin, unlike carbamazepine, can be administered intravenously, crescendo attacks can be controlled rapidly with a loading dose of 12 mg/kg at 50 mg/min. A combination of carbamazepine and phenytoin has been claimed to be effective when either drug alone is inadequate.
Valproic acid
The effectiveness of valproic acid for the pain of trigeminal neuralgia was initially evaluated in a single, open-label trial, where it demonstrated some benefit [15]. In a subsequent double-blind trial, Desai et al. [16] studied the effect of sodium valproate 800 to 1600 mg/day in patients with trigeminal neuralgia resistant to carbamazepine. During three months of follow-up, eight out of 10 patients receiving valproic acid alone reported a 50 to 75% improvement (as defined as a reduction in the frequency of attacks), as compared to only two out of 10 control patients receving carbamazepine alone.
Lamotrigine
In a double-blind, placebo-controlled, crossover study, lamotrigine, at a maintenance dose of 400 mg/day, was administered as add-on treatment to 14 patients with trigeminal neuralgia refractory to carbamazepine or phenytoin [17]. Lamotrigine was significantly superior to placebo (P = 0.011), based on a composite efficacy index. Seven out of 13 patients experienced unwanted effects, including dizziness, somnolence, constipation, nausea and diplopia.
Gabapentin and Topiramate
Small, open-label studies have suggested that gabapentin and topiramate may be effective in the treatment of refractory trigeminal neuralgia in patients with multiple sclerosis [18, 19]. Gabapentin, 900 to 2 400 mg/day, induced complete pain relief in six out of seven patients [18]. Pain relief reached the maximum effect within two weeks and was maintained for up to one year. Topiramate, 200 to 300 mg/day, had a beneficial effect in five out of six multiple sclerosis patients [19]. Relief of pain typically occurred within one week of therapy and patients remained pain-free for at least six months.
Neuropathic pain
Neuropathic pain is a form of chronic pain caused by injury to or disease of central and peripheral nervous system. It includes trigeminal neuralgia, already covered in the previous section, neuralgias affecting other cranial or peripheral nerves (glossopharyngeal, superior laryngeal), postherpetic neuralgia, diabetic neuropathy, central post-stroke pain syndrome, phantom limb pain, tabetic pain, cancer pain and others. Neuropathic pain responds poorly to standard therapeutic approaches for pain and to standard doses of opioid analgesics [20, 21]. Over the past two decades, knowledge of the pathogenesis of neuropathic pain has increased significantly. Neuropathic pain, whether of peripheral or central origin, is characterized by a neuronal hyperexcitability in damaged areas of the nervous system [20-22]. Such a hyperexcitability is due to a series of molecular changes in the peripheral nociceptor, dorsal root ganglia, the dorsal horn of the spinal cord, and the brain. These changes include abnormal expression of sodium channels, increased activity at glutamate receptors, changes in gamma-aminobutyric acid inhibition, and an alteration of calcium influx into cells. The similarities between the biochemical and molecular changes observed in some epilepsy and neuropathic pain models justify the use of AEDs in the management of neuropathic pain. Carbamazepine and phenytoin were the first AEDs to be used in controlled clinical trials (Table 2). The availability of newer AEDs has marked a new era in the treatment of neuropathic pain. While gabapentin has the most clearly documented analgesic effect, other agents, including lamotrigine, topiramate and pregabalin, have also been under investigation (Table 2).
Table 2. Randomized clinical trials of anti-epileptics for the treatment of neuropathic pain.
Study (Ref.) |
No. treated (diagnosis) | Design | Daily dosage | Duration | Main outcome |
---|---|---|---|---|---|
Carbamazepine (CBZ) | |||||
Rull et al., 1969 [23] | 30 (diabetic neuropathy) | db, pc, co | Up to 600 mg | two weeks | Responders: CBZ 28/30; placebo 19/30 |
Gomez-Perez et al., 1996 [24] | 16 (diabetic neuropathy) | db, pc, co | CBZ: 600 mg, fluphenazine + nortriptyline: 1.5 mg + 30 mg | four weeks | No difference between treatments |
Gerson, 1977 [25] | 29 (post-herpetic neuralgia) | ac, co | CBZ + clomipramine: 150-1 000 mg + 10-75 mgTCN | eight weeks | CBZ + clomipramine more effective than TCN |
Kezkes and Basheer, 1980 [26] | 40 (acute herpes zoster) | db, ac, pg | CBZ: 400 mg, prednisolone: 40 mg | four weeks | CBZ less effective than prednisolone in reducing pain severity |
Leijon and Boivie, 1989 [27] | 15 (stroke) | db, pc, ac, pg | CBZ: up to 800 mg, amitriptyline: up to 75 mg | four weeks | Responders: CBZ 5/14; amitriptyline 10/15; placebo 1/15 |
Tripathi and Kaushick, 2000 [28] | 12 (Guillain-Barrè syndrome) | db, pc, co | 300 mg | seven days | CBZ more effective than placebo |
Phenytoin (PHT) | |||||
Saudek et al., 1977 [30] | 12 (diabetic neuropathy) | db, pc, co | 300 mg | 23 weeks | PHT similar to placebo |
Chadda and Mathur, 1978 [31] | 40 (diabetic neuropathy) | db, pc, co | 300 mg | two weeks | Responders: PHT 28/38; placebo 10/38 |
Lockman et al., 1973 [32] | eight (Fabry’s disease) | db, pc, ac, co | PHT: up to 300 mg, Aspirin: 1 700 mg | three weeks | PHT superior to aspirin in relieving subjective pain |
McCleane, 1999 [33] | 20 (acute exacerbation of neuropathic pain) | db, pc, co | 15 mg/kg infusion | two hours | PHT superior to placebo in decreasing burning, shooting and overall pain |
Gabapentin (GBP) | |||||
Backonja et al., 1998 [36] | 165 (diabetic neuropathy) | db, pc, pg | 900-3 600 mg | eight weeks | Response rate: GBP 47.6%; placebo 20.0% |
Rowbothamet al., 1998 [37] | 229 (post-herpetic neuralgia) | db, pc, pg | 900-3 600 mg | eight weeks | Response rate: GBP 29.4%; placebo 12.1% |
Morello et al., 1999 [38] | 21 (diabetic neuropathy) | db, ac, co |
900-1 800, amitriptyline 25-75 |
six weeks | Response rate: GBP 52%; amitriptyline 67% |
Rice and Maton, 2001 [39] | 334 (post-herpetic neuralgia) | db, pc, pg | 1 800 mg 2 400 mg | seven weeks | Response rate: GBP 1800 32.2%; GBP 2400 34.3%; placebo 14.4% |
Serpell et al., 2002 [40] | 305 (various neuropathic pain syndromes) | db, pc, pg | 900-2 400 mg | eight weeks | Response rate: GBP 21.9%; placebo 14.9% |
Lamotrigine (LTG) | |||||
Simpson et al., 2000 [45] | 42 (painful HIV-associated neuropathy) | db, pc, co | 300 mg | 14 weeks | LTG more effective than placebo in reducing pain |
Vestergardet al., 2001 [46] | 30 (central post-stroke pain) | db, pc,co | 200 mg | eight weeks | LTG more effective than placebo in reducing pain |
McCleane, 1999 [47] | 100 (various neuropathic pain conditions) | db, pc, pg | 200 mg | eight weeks | LTG had no effect in reducing pain |
Carbamazepine
Six randomized clinical trials have evaluated the efficacy of carbamazepine, administered at daily dosages ranging from 150 to 1 000 mg, in neuropathic pain other than trigeminal neuralgia [23-28]. Two of these studies were performed in patients with painful diabetic neuropathy: in one study the drug was compared with placebo [23], and in the other with nortiptyline-fluphenazine [24]. Carbamazepine was more effective than placebo and similar to the tricyclic-neuroleptic combination in the treatment of diabetic neuropathy. The efficacy of carbamazepine in patients with postherpetic neuralgia was assessed in two studies [25, 26]. In the first trial, the combination carbamazepine-clomipramine was more effective than transcutaneous nerve stimulation [25], while in the second, the drug was less effective than prednisolone [26]. In one study of patients with central post-stroke pain, there was no statistically significant difference between carbamazepine and placebo in pain relief [27]. In a more recent double-blind, placebo-controlled, crossover study in patients with Guillain-Barrè syndrome in the intensive care unit, the pain score was significantly (P < 0.001) lower during carbamazepine than placebo phase [28]. Case reports and open series indicate that carbamazepine may be effective also in glossopharyngeal neuralgia, phantom limb pain, multiple sclerosis and thalamic syndrome [29].
Phenytoin
Few randomized placebo-controlled studies have evaluated the efficacy of phenytoin, administered orally at an average dose of 300 mg/day, in patients with diabetic neuropathy [30, 31] and Fabry’s disease [32]. While the results of studies in patients with diabetic neuropathy were conflicting, phenytoin was more effective than aspirin 1 700 mg/day and placebo in patients with Fabry’s disease. In a recent double-blind, placebo-controlled, crossover study, a two hour intravenous infusion of 15 mg/kg phenytoin showed a significant analgesic effect in acute exacerbation of neuropathic pain [33]. Although these studies provide some evidence for the efficacy of phenytoin in the management of neuropathic pain, data on its utility are still lacking.
Gabapentin
Gabapentin has been recently approved in several countries for
the symptomatic treatment of neuropathic pain in adults,
particularly diabetic neuropathy and postherpetic neuralgia.
Although its mode of action is not fully understood, gabapentin
appears to have a unique effect on voltage-dependent calcium ion
channels at the postsynaptic dorsal horns and may, therefore,
interrupt a series of events that possibly lead to the experience
of a neuropathic pain sensation [34]. Data from case reports, open
studies and randomized, placebo-controlled trials have documented
the efficacy of gabapentin in the treatment of painful diabetic
neuropathy, postherpetic neuralgia, and other neuropathic pain
syndromes [35]. In particular, gabapentin appears to relieve
symptoms of allodynia, burning pain, shooting pain, and
hyperesthesia.
In a double-blind trial, 165 patients with chronic painful
diabetic neuropathy were randomly assigned to receive gabapentin
(titrated from 900 to 3 600 mg/day or maximum tolerated
dosage) or placebo [36]. At the eight-week study end point, for the
intention-to-treat population, the gabapentin group had a
significant improvement (P < 0.001) in mean
daily pain scores compared with the placebo group. Pain relief was
already observed during the second week of treatment after the
gabapentin dosage reached 1 800 mg/day and was maintained
after further dosage increase and for the overall duration of the
study. In a trial with a very similar design, gabapentin was
compared with placebo in 229 patients with postherpetic
neuralgia [37]. The average daily pain score, the primary efficacy
parameter, was significantly reduced
(P < 0.001) in the gabapentin-treated group
compared with the placebo-treated group from week two until the end
of study week eight, without signs of tolerance. In both studies,
symptoms frequently associated with chronic pain were also
evaluated; sleep, mood and quality of life were improved during
gabapentin treatment. One randomized, double-blind crossover study
compared gabapentin (900 to 1 800 mg/day) and
amitriptyline (25 to 75 mg/day) in patients with peripheral
diabetic neuropathy [38]. At the end of the six-week study period,
both drugs provided a significant and comparable analgesic effect.
In the gabapentin-treated group, sedation and dizziness were the
most common adverse effects, while in the amitriptyline group dry
mouth and weight gain were the most frequent. In a seven-week,
randomized, double-blind, placebo-controlled trial, the efficacy
and tolerability of fixed doses of gabapentin, 1 800 and
2 400 mg/day were assessed in 334 patients with
postherpetic neuralgia [39]. At the end of the study, the
difference in mean pain scores between gabapentin and placebo was
18.8% for the 1 800 mg dose and 18.7% for
2 400 mg dose (P < 0.01, both
gabapentin groups versus placebo). Statistically significant
reductions in daily pain scores for gabapentin and placebo were
already achieved at week one, when the gabapentin dose was
1 200 mg/day. Gabapentin was well tolerated, with the
most common adverse effects being dizziness and somnolence. A large
eight-week, double blind, placebo-controlled trial evaluated the
efficacy and safety of gabapentin, 900 to 2 400 mg/day,
in patients with a wide range of neuropathic pain syndromes with at
least two of the following symptoms: allodynia, burning pain,
shooting pain or hyperalgesia [40]. At the end of treatment, mean
daily pain scores were significantly reduced with gabapentin
compared with placebo (P < 0.05). The most
common adverse effects were mild to moderate dizziness and
somnolence, most of which were transient and occurred during the
titration phase. Gabapentin also appears to be effective 3 in
a variety of other painful neuropathic syndromes such as
neuropathic pain after traumatic spinal cord injury [41],
Guillain-Barrè syndrome [42], postamputation phantom limb pain [43]
and postoperative pain [44].
Treatment with gabapentin should be started at a dose of
900 mg/day (300 mg on day 1 600 mg on day two,
and 900 mg on day three). Additional titration to
1800 mg/day is recommended for greater efficacy. Doses of up
to 3 600 mg/day may be needed in some patients. Adverse
effects are typically mild to moderate and usually tend to
disappear within approximately 10 days from the beginning of
treatment.
In summary, based on the positive results of these studies, its
favourable tolerability profile and low potential for drug
interactions, gabapentin should be considered an important agent in
the management of neuropathic pain syndromes.
Lamotrigine
There is a limited and conflicting evidence on the effectiveness of lamotrigine in the management of a variety of painful neuropathic syndromes. In a double-blind, placebo-controlled study of 42 patients with HIV-associated, painful neuropathy, the mean reduction in pain score from baseline to week 14 was significantly greater (P < 0.05) in patients treated with lamotrigine at 300 mg/day, than in those receiving placebo [45]. However, the frequency of rash was greater than in lamotrigine studies in epilepsy. In addition, a placebo-controlled, crossover, eight-week trial, showed that lamotrigine, 200 mg/day, was more effective than placebo (P < 0.01) in 27 patients with central post-stroke pain [46]. In contrast to the positive results of these studies, in a randomized, double-blind, placebo-controlled trial, lamotrigine at doses of up to 200 mg/day had no analgesic effect in 100 patients with a variety of neuropathic pain conditions [47].
Topiramate
Evidence from pilot controlled trials and open-label studies indicates that topiramate may provide consistent pain relief in patients with neuropathic pain, especially diabetic neuropathy, in whom other analgesics, including other antiepileptic drugs, have failed [48]. Further studies in randomized controlled trials are needed to document these initial observations.
Pregabalin
In a recent, multicenter, eight-week, double-blind, placebo-controlled trial in 173 patients with postherpetic neuralgia, pregabalin, a new AED not yet available for clinical use, administered at doses of 300 or 600 mg/day, was significantly more effective than placebo (P = 0.0001) in reducing pain [49].
Migraine
The pharmacological treatment of migraine may be acute (abortive, symptomatic) or preventive (prophylactic). While triptans and ergotamine derivatives are the primary agents for migraine attacks, established drugs currently used for the prevention of migraine include beta-blockers, calcium channel antagonists, antidepressants, serotonin antagonists and nonsteroidal anti-inflammatory drugs. In recent years, new agents, mostly AEDs, have been investigated based on their action on the metabolism of GABA and glutamic acid and, possibly, on a presumed neurogenic vascular effect [50]. In this respect, there is an inceasing recognition of the role that cortical hyperexcitabilty and an imbalance between GABAergic inhibition and amino acid-mediated excitation may play in the pathophysiology of migraine. To date, valproic acid is the only AED approved for migraine prevention, while other newer agents, such as gabapentin and topiramate, are being evaluated (Table 3).
Table 3. Randomized clinical trials of anti-epileptics for the treatment of migraine.
Study (Ref.) |
No. treated | Design | Daily dosage | Duration | Main outcome |
---|---|---|---|---|---|
Valproic acid (VPA) | |||||
Hering and Kuritzki, 1992 [52] | 29 | db, pc, co | 800 mg | eight weeks | Response rate: VPA 86% |
Jensen et al., 1994 [53] | 43 | db, pc, co | 1 000-1 500 mg | 12 weeks | Response rate: VPA 50%; placebo 18% |
Mathew et al., 1995 (54) | 107 | db, pc, pg | 500-1 500 mg | 12 weeks | Response rate: VPA 48%; placebo 14% |
Klapper 1997 [55] | 176 | db, pc, pg | 500-1 500 mg | 12 weeks | Response rate: VPA 43%; placebo 21% |
Topiramate (TPM) | |||||
Edwards et al., 2000 [58] | 30 | db, pc, pg | 200 mg | 18 weeks | Response rate: TPM 47%; placebo 7% |
Storey et al., 2001 [59] | 40 | db, pc, pg | 25-200 mg (mean 125 mg) |
16 weeks | Response rate: TPM 26%; placebo 10% |
Gabapentin (GBP) | |||||
Mathew et al., 2001 [60] | 143 | db, pc, pg | 900-2 400 mg | 12 weeks | Response rate: GBP 46% placebo16% |
Lamotrigine (LTG) | |||||
Steiner et al., 1997 [63] | 77 | db, pc, pg | 200 mg | 12 weeks | Attack rates reduced by 11% with LTG and 32% with placebo |
Valproic acid and divalproex sodium
Valproic acid (sodium valproate) was approved for migraine
prophylaxis by the US Food and Drug Administration (FDA) in 1996.
It is usually used in the form of divalproex sodium, an oligomeric
complex composed of valproate sodium and valproic acid in a
1:1 ratio. The mechanism of action of valproic acid in
migraine prophylaxis may be related to facilitation of GABAergic
neurotransmission and attenuation of neurogenic inflammation
[51].
Double-blind, placebo-controlled studies and a variety of open
trials reviewed by Silberstein [51], have documented that valproic
acid is an effective preventive treatment for migraine. In summary,
randomized, placebo-controlled trials [52-55] showed that response
rate among patients treated with valproic acid, 800 to
1 500 mg/day, ranged from 43 to 86% compared with 14 to
21% in those receiving placebo. The drug seemed to reduce the
number, severity and duration of migraine attacks with a modest
dose-response effect. Adverse effects, mostly gastrointestinal,
occurred in 19 to 86% of cases (7 to 79% with placebo). Data from
the two multicenter studies [54, 55] indicated that valproic acid
was equally as effective in migraine with aura as in migraine
without aura.
At present, there are no large comparative studies of valproic
acid and traditional agents for the preventive treatment of
migraine. In a small single-blind, crossover comparative study of
divalproex, propranolol and placebo in 37 patients with
migraine without aura, assessment of migraine frequency revealed a
significant response (defined as a greater than 50% reduction in
either mean migraine frequency or mean number of days with migraine
compared with baseline) in 66% of patients treated with divalproex,
dose range from 750 to 2 000 mg/day, in 63% of patients
treated with propranolol, dose range from 120 to 240 mg/day,
and in 19% of those receiving placebo [56].
In an open-label, long-term efficacy and safety study of
divalproex for migraine prophylaxis, 163 patients were treated
for up to three years [57]. The starting dose of divalproex was
500 mg/day, with adjustment of dose and frequency possible
after one to three days. Treatment lasted more than 180 days
for 71% of patients and more than 360 days for 48% of
patients. Improvements in the four-week, change-from-baseline
migraine rates were seen during each of the three- and six-month
time intervals. Nausea (42%), infection (39%), alopecia (31%), and
tremor (28%) were the most commonly reported adverse effects, but
most of these resolved spontaneously with continuing treatment. The
incidence of tremor, however, remained relatively constant at 20 to
30% throughout the study.
Divalproex has been used in the acute treatment of migraine. Small
open studies have suggested that intravenous valproic acid is
effective in acute migraine treatment [51]. Moreover, evidence from
open-label trials has indicated that divalproex may be useful as
preventive therapy in patients with episodic or chronic cluster
headache [51].
The following practical recommendations have been proposed for the
optimal use of valproic acid in migraine [51]:
– before initiating treatment, a physical medical examination
and a thorough medical history, with special attention to hepatic,
hematological and bleeding abnormalities, should be performed;
– to minimize gastrointestinal side effects an enteric-coated
formulation should be preferably used. The starting dose is
250 mg at bedtime, slowly increasing up to
500-750 mg/day;
– follow-up serum concentrations of valproic acid should be
obtained to evaluate compliance and toxicity;
– during the first six-nine months patients should be
controlled on a regular basis (every one-two months);
– it is not necessary to monitor blood and urine in healthy
and asymptomatic patients receiving monotherapy;
– if mild elevation of serum hepatic aminotransferase levels
occurs, valproic acid should be continued at the same dosage or a
lower dosage until enzyme levels normalize. If the hepatic
aminotransferase elevations are much higher, valproic acid has to
be discontinued;
– if tremor (which may occur in 10% of treated patients) is
bothersome, the dose of valproic acid should be reduced or,
alternatively, propranolol may be used;
– valproic acid should be avoided in very young children with
a suspicion of a metabolic disorder, in patients with preexisting
liver disease and in pregnant women.
Topiramate
Topiramate is a promising agent for migraine prevention. Two,
relatively small, placebo-controlled trials have evaluated the
effect of topiramate prophylaxis in patients with migraine. In the
first trial [58], 30 patients who had migraine with or without
aura were randomized to topiramate prophylaxis
(n = 15) or placebo (n = 15). The
study included a 4-week baseline phase, followed by a six-week
titration and a 12-week maintenance phase. Eleven patients reached
a topiramate dose of 200 mg/day (mean 173 mg/day). After
18 weeks of treatment, the mean 28-day migraine frequency was
reduced by 29% in patients receiving topiramate and by 7% in those
receiving placebo. Percentage of responders (subjects
with = 50% reduction in 28-day migraine frequency) were
47% in the topiramate group and 7% in the placebo group
(P = 0.035). Therapy was well-tolerated and
discontinuation rates were similar in the two study groups. Adverse
effects included paresthesia, diarrhea, altered taste and
somnolence. The second study [59] lasted 20 weeks (baseline,
titration and maintenance phase of four, eight, and eight weeks),
and included 40 patients who were randomly assigned to receive
topiramate (n = 19), dose ranging from 25 to
200 mg/day, or placebo (n = 21). The mean
28-day migraine frequency was reduced by 36% in topiramate-treated
patients as compared with 14% in placebo recipients
(P = 0.004). In addition, 26% of patients on
topiramate and 9.5% of those on placebo achieved a 50% reduction in
migraine frequency. Adverse effects that occurred more frequently
in topiramate-treated patients included paresthesia, weight loss,
altered taste, anorexia and memory impairment.
In summary, the available data suggest that topiramate may be
effective in migraine prevention. Further evaluation in
double-blind, placebo-controlled trials with larger populations is
needed to confirm these preliminary findings.
Gabapentin
Gabapentin is under investigation for its possible use for the prevention of migraine. In a recent 12-week multicentre prophylaxis trial of 143 patients with migraine, randomized to receive either gabapentin (n = 98) or placebo (n = 45), the median four-week migraine rate was 2.7 for patients treated with gabapentin, maintained on a stable dosage of 2 400 mg/day, and 3.5 for those treated with placebo (P = 0.006), compared with 4.2 and 4.1, respectively, during the baseline period [60]. Additionally, the proportion of patients showing at least 50% reduction in the migraine rate was 46.4% with gabapentin and 16.1% with placebo (P = 0.008). Dizziness, somnolence, and asthenia were the most commonly reported adverse effects in the gabapentin group. The Authors concluded that gabapentin was an effective and well-tolerated prophylactic agent for migraine. However, the use of a modified’ intention-to-treat approach represents an important limitation of this study. Therefore, despite possible advantages of gabapentin over valproate in terms of tolerability and drug interaction potential, there are still no convincing data to support the use of gabapentin for the prophylaxis of migraine.
Lamotrigine
There is limited information concerning the possible use of lamotrigine in migraine treatment. While two open studies suggested that lamotrigine may be useful for preventing aura associated with migraine [61, 62], the results of a 12-week, double-blind, placebo-controlled trial in which 37 patients received lamotrigine, 200 mg/day, and 40 received placebo, indicated that lamotrigine is not effective for migraine prophylaxis [63].
Essential tremor
Essential tremor is a progressive neurological disorder characterized by oscillating movements caused by alternative contraction of agonist and antagonist muscles. Beta-receptor blocking agents (propranolol and analogues) and the anticonvulsant primidone are considered first-line pharmacological treatment in patients with essential tremor [64]. The new anticonvulsant agents gabapentin and topiramate may represent alternative therapeutic options.
Primidone
Several open and randomized clinical trials, reviewed by Koller et al. [65], have documented the efficacy of primidone in essential tremor. The drug was used at dosages ranging from 50 to 1 000 mg/day. The impact of treatment was evaluated clinically and reduction of tremor was assessed with an accelerometer. Daily doses of primidone 250, 750 and 1 000 mg showed comparable efficacy and caused a tremor decrease by 60 to 70%. Adverse effects such as somnolence, fatigue, vertigo, nausea and unsteadiness, were often experienced at the beginning of treatment unless low doses (25 to 50 mg/day) were used and titrated slowly. In the only study comparing primidone with propranolol, the two agents were found to be equally effective [66]. Unlike primidone, phenobarbital and phenylethylmalonamide, the active metabolites of primidone, showed little or no evidence of efficacy in essential tremor.
Other antiepilepics
Other AEDs that may be useful in the treatment of essential tremor include gabapentin and topiramate. In a double-blind, placebo-controlled trial in 20 patients with essential tremor, gabapentin, 1 800 mg/day, added to baseline antitremor medication for 2 weeks, had only a limited treatment benefit [67]. By contrast, in a double-blind, three-way placebo- and propranol-controlled crossover study in 16 patients with essential tremor, gabapentin, 1 200 mg/day, and propranolol, 120 mg/day, demonstrated significant and comparable efficacy in reducing tremor [68]. In a recent double-blind, placebo-controlled, crossover trial, topiramate, 400 mg/day or maximum tolerated dose, given as monotherapy or adjunctive treatment, showed a significant effect in 24 patients with essential tremor [69]. The most common adverse effects were appetite suppression/weight loss and paresthesias.
Other nonepileptic neurological conditions
In addition to the previously mentioned categories, AEDs appear to be promising in the treatment of a variety of other nonepileptic neurological conditions, including myotonia, spasticity, amyotrophic lateral sclerosis, neonatal cerebral haemorrhage, Parkinson’s disease [1]. However, evidence for the efficacy of AEDs in these disorders is still inadequate and most studies are too small to detect a true difference between treatments.
Use of antiepileptic drugs in psychiatric disorders
In the last three decades, AEDs have become an integral part of the pharmacological treatment of many psychiatric conditions, in particular bipolar disorder, and an ever-increasing number of other potential indications, ranging from impulse control disorders to aggressive behavior, substance use disorders, and refractory anxiety disorders.
Bipolar disorder
Bipolar disorder is a severe, chronic and potentially
life-threatening illness of recurrent mood episodes, i.e., mania,
hypomania, depression and mixed states (concomitant manic and
depressive symptoms), and rapid cycling (four or more episodes per
year). It is subdivided into bipolar I (manic and depressive
episodes) and bipolar II disorder (hypomanic and depressive
episodes).
Lithium has been, for many years, the treatment of choice for
bipolar disorder. The growing awareness of the limitations of
lithium treatment prompted the search for alternative treatment
options. In this regard, the discovery of the mood-stabilizing
properties of some AEDs has significantly broadened the array of
treatment options for bipolar disorder. AEDs, such as carbamazepine
and valproic acid, have joined lithium as standard, brief-term
treatment of manic episodes and mixed-states, and long-term
prevention of relapses of bipolar disorder. Notwithstanding their
efficacy and relative safety, even carbamazepine and valproic acid
have important limitations and negative effects. A significant
subgroup of bipolar patients, especially those characterized by a
very unstable or chronic course, shows varying degrees of
resistance to these drugs. Moreover, both carbamazepine and
valproic acid may cause side effects, such as weight gain and
impairment of cognitive functioning, which may significantly reduce
compliance, and compromise long-term treatment. In addition,
long-term tolerance to the mood stabilizing effect has been
reported for lithium, carbamazepine and valproic acid, either in
monotherapy or in combination [70, 71]. Finally, traditional mood
stabilizers have shown significant efficacy on the (hypo)manic
phases of bipolar disorder, but only marginal efficacy on the
depressive phases, that respond less to these treatments and often
require the association of antidepressants, which often themselves
become the cause of side effects, manic switches, cycle
acceleration, and chronicity.
The availability of a new generation of AEDs has broadened the
therapeutic choices for the treatment of bipolar patients who are
resistant or intolerant to traditional mood stabilizers. Among the
new AEDs, 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, while preliminary evidence exists
also for tiagabine and zonisamide. In general, these drugs have a
more favourable tolerability profile and a lower potential for drug
interactions as compared to traditional mood stabilizers, and this
may significantly improve compliance with treatment. As
carbamazepine and valproic acid are well established agents in the
treatment of bipolar disorder, in this section more emphasis is
given to studies documenting the potential role of newer AEDs in
this condition. Therefore, only results of randomized clinical
trials on the use of new AEDs in patients with bipolar disorder are
reported in Table 4.
Study (Ref.) | No. treated (diagnosis) | Design | Dosage | Duration | Main outcome |
---|---|---|---|---|---|
Lamotrigine (LTG) | |||||
Calabrese et al., 1999 [110] |
195 (bipolar I: major depressive episode) | db, pc, pg | 50-200 | seven weeks | LTG 50 mg/day: 41%, LTG 200 mg/day: 51%, placebo: 26% |
Calabrese et al., 2000 [111] | 182 (rapid-cycling bipolar disorder) | db, pc, pg | 50-400 mg (mean: 288 mg/day) | 26 weeks | LTG better than placebo on a number of outcome measures |
Bowden et al., 2003 [113] | 175 (recently manic or hypomanic patients with bipolar I disorder) | db, pc, ac, pg | LTG: 100-400 mg/day, Lithium: 0.8-1.1 mEq/L | 18 months | LTG effective in long-term maintenance, particularly for prophylaxis of depression |
Oxcarbazepine (OXC) | |||||
Muller and Stoll 1984 [115] |
20 (acute mania) | db, ac, pg |
OXC: 900-1 200 mg/day, haloperidol: 15-20 mg/day |
two weeks | Both groups showed a significant improvement of manic symptoms, faster in the OXC group |
Emrich 1985 [114] |
12 (acute mania) | db, ac, pg, co | OXC: 1 800-2 100 mg/day, VPA: 1 800-3 800 mg/day | Not reported | VPA and OXC showed a significant improvement of manic symptoms in comparison with placebo |
Emrich 1990 [116] |
38 (acute mania) | db, ac, pg | OXC: 2 400 mg/day (mean dose), haloperidol: 42 mg/day (mean dose) | two weeks |
Both drugs resulted in a statistically significant improvement; no significant difference in efficacy between the two groups |
52 (acute mania) | db, ac, pg | OXC: 1 400 mg/day (mean dose), Lithium: 1 100 mg/day (mean dose) | two weeks |
Both drugs resulted in a statistically significant improvement; no significant difference in efficacy between the two groups |
|
Gabapentin (GBP) | |||||
Frye et al., 2000 [112] |
31 (bipolar patients refractory to standard mood stabilizers) | db, pc, ac, co | GBP: mean: = 3 987 mg/day, LTG: mean = 274 mg/day | six weeks | LTG superior to placebo; No significant difference between GBP and placebo |
Pande et al., 2000 (126) |
116 (patients with resistant bipolar disorder) | db, pc, ao | 900-3 600 mg/day | eight weeks | No statistically significant difference between adjunctive treatment with GBP and placebo |
Topiramate (TPM) | |||||
Mc Intyreet al., 2000 [141] | 36 (bipolar I and II depression) | sb, ac, pg | TPM: 50-300 mg/day, bupropion SR: 100-400 mg/day | eight weeks | TPM improves depressive symptoms and produced more weight loss than buproprion |
Carbamazepine
At least 12 double-blind randomised controlled trials were
reported in the 80s and early 90s, showing that carbamazepine is
superior to placebo and comparable to lithium and antipsychotics in
the treatment of acute mania [72-83]. However, only six of these
studies [72-75, 78, 83] have not been biased by the concomitant use
of lithium and antipsychotics. Summarizing this literature [84,
85], it has been possible to conclude that: 1) carbamazepine
is effective in 50% of the cases, versus 56% of lithium and
61% of neuroleptic monotherapy (these differences are not
statistically significant); 2) carbamazepine acts more rapidly
than lithium, and it similar to antipsychotics in its antimanic
effects; 3) in general, carbamazepine is better tolerated than
lithium and antipsychotics in patients that remain in treatment,
although the number of drop-out for adverse events is similar. In
responders, the blood levels are similar to those utilized in
epilepsy, 4-15 µg/mL, with daily dosages ranging from 400 to
2 000 mg/day.
Three, small, double-blind, placebo-controlled, cross-over studies
examined the efficacy of carbamazepine [82, 86, 87] in a total of
40, bipolar, depressed patients; of these patients 27 (68%)
responded to carbamazepine treatment, and placebo substitution led
to relapse of the depressive symptoms in 50% of the cases.
The efficacy of carbamazepine in the maintenance treatment of
bipolar disorder was examined in only a small, double-blind,
placebo-controlled trial (carbamazepine: n = 12;
placebo: n = 10) [88]. Results indicated that 60%
of patients randomized to carbamazepine, and 22% randomized to
placebo were stable during the one-year study period. A number of
other controlled studies compared carbamazepine with lithium, and
reported that up to two-thirds of patients responded to
carbamazepine [79, 89-92].
In summary, carbamazepine seems to have some efficacy in the
long-term, maintenance treatment of bipolar disorder, but further
studies are needed before firm conclusions can be drawn. The drug
seems to be more effective in preventing manic rather than
depressive recurrences, and long-term tolerance to this therapeutic
effect (tachyphylaxis), has been described [93]. However, it is
difficult to exclude the possibility that the loss of efficacy
observed with carbamazepine during maintenance treatment of
selected bipolar patients, might be due to the progression of the
illness, rather than the development of tolerance. Interestingly,
some of the predictors of poor lithium response, such as the
severity of the manic symptomatology, the presence of rapid cycling
(four or more episodes/year), or mixed states, and the lack of
positive family history for mood disorders [94, 95], have been
associated with a favourable response to carbamazepine.
Valproic acid
Although valproic acid has been used in bipolar patients
resistant or intolerant to lithium or carbamazepine for its safety
and tolerability, it is today considered the first choice drug for
the treatment of acute mania. Numerous open-label and controlled
studies have clearly indicated that valproic acid is effective in
the treatment of acute mania [96-101]. In controlled trials
[97-101], valproic acid has been shown to be superior to placebo
and comparable to lithium in the short-term treatment of manic
episodes; about 60% of patients treated with valproic acid showed
marked to moderate improvement of acute symptomatology. The
antimanic response was obtained two weeks after that the blood
level of valproic acid had reached 50 µg/mL or more. However,
there is preliminary evidence of a more rapid antimanic action when
using high doses from the beginning. In an open study with blind
evaluation of the outcome, 19 manic patients were treated with
20 mg/kg/day of valproic acid (oral loading) from the
first day of treatment; 10 (53%) of these patients presented a
significant clinical response after five days, with minimal side
effects [102].
A placebo-controlled, parallel-design study, examined the efficacy
of valproic acid monotherapy in acute bipolar depression [103].
After a single-blind placebo lead-in for up to 14 days,
patients were randomized to treatment with valproic acid or placebo
for eight weeks. Intent-to-treat analysis indicated that nine out
of 21 (43%) subjects randomized to valproic acid and six out of 22
(27%) randomized to placebo met criteria for recovery
(P = 0.4). Mean changes from baseline in the
Hamilton Depression Rating Scale (HDRS) scores were greater in the
valproic acid group, and were significant at weeks two and five,
but not at the end-point, compared with the placebo group. The
negative findings in this study could be due to a smaller sample
size. A double-blind study compared the efficacy of adding a second
mood stabilizer versus addition of paroxetine in the treatment of
bipolar depression [104]. Twenty-seven patients with bipolar
depression, on either lithium or valproic acid, were randomly
assigned to addition of a second mood stabilizer (lithium for those
on valproic acid and valproic acid for those on lithium), or
paroxetine for six weeks. Both groups improved with no significant
difference between the groups. Combination of lithium plus valproic
acid would be an appropriate strategy for bipolar 1 depressed
patients with a previous history of severe or refractory manic
episodes, as the goal in such patients would be to relieve
depressive symptoms with the least risk of inducing a manic
switch.
In a placebo-controlled trial of the efficacy of valproic acid in
the maintenance treatment of bipolar disorder, Bowden et al.
[105] randomized 372 patients who met recovery criteria within
three months of an index manic episode, to maintenance treatment
with divalproex, lithium, or placebo in a 2:1:1 ratio. On the
primary efficacy measure of time-to-any-mood episode, the
divalproex group did not differ significantly from the placebo
group. However, divalproex was superior to placebo in terms of
lower rates of discontinuation for either a recurrent mood episode
or depressive episode. Divalproex was also superior to lithium in
terms of a longer duration of successful prophylaxis in the study
and less deterioration in depressive symptomatology. A controlled
prospective study compared the efficacy of valproic acid
(n = 78) with lithium (n = 72) in
150 patients (121 were bipolar and 29 were
unipolar), over a two-year period [106]. The number of episodes
decreased from 4.12 during the two years prior to the study to
0.51 in the valproic acid group, and from 3.92 to 0.61 in
the lithium group; there was no significant difference in efficacy
between the two groups. There were, however, fewer drop-outs (10%)
in the valproic acid group compared with the lithium group
(25%).
In summary, valproic acid is the first choice drug for the
treatment of acute mania. In addition, it seems to be effective in
the maintenance treatment of bipolar disorder, but this needs to be
confirmed in further double-blind trials. Predictors of response to
valproic acid seem to include rapid cycling course, depressive
symptoms during mania, late age-at-onset, and mania associated with
mental retardation or secondary to medical or neurological illness
[107].
Lamotrigine
Initial open prospective trials provided evidence that
lamotrigine may be an effective treatment option for patients with
refractory forms of bipolar disorder [108]. More recently, a
considerable number of systematic studies has indicated that
lamotrigine may be an efficacious and well-tolerated treatment in
bipolar disorder. Its efficacy principally addresses acute bipolar
depression and continuation treatment, especially prophylaxis
against depressive symptomatology [109]. On the other hand,
lamotrigine has not been shown to have clear efficacy in the
treatment of mania or unipolar depression.
With regard to bipolar depression, the double-blind seven-week
comparison between lamotrigine at 50 or 200 mg/day and
placebo, in 195 bipolar one patients experiencing a major
depressive episode, showed that depressive symptomatology showed a
significant improvement in both 50 and 200 mg/day groups
[110]. According to the Clinical Global Impression (CGI) scale, 41%
of the patients receiving 50 mg/day and 51% of those taking
200 mg/day of lamotrigine reported a clinical remission
versus 26% of subjects treated with placebo. The incidence
of rash was comparable between the lamotrigine and placebo groups,
and there were no reports of severe rash among study participants.
In a controlled study of patients with rapid-cycling bipolar
disorder, Calabrese et al. [111] compared lamotrigine and
placebo during a 26-week randomised phase. Lamotrigine was better
than placebo on a number of outcome measures, in particular in
bipolar II patients. These findings support the efficacy of
lamotrigine in rapid cycling bipolar II disorder, which is often
resistant to standard mood stabilizers, and are consistent with
data reported by Frye et al. [112] comparing lamotrigine,
gabapentin and placebo in resistant bipolar patients.
In a recent study [113], the long-term efficacy and tolerability
of lamotrigine was compared with lithium and placebo in recently
manic or hypomanic patients with bipolar I disorder. After an
eight- to 16-week open-label phase during which treatment with
lamotrigine was initiated and other psychotropic drug regimens were
discontinued, patients were randomized to lamotrigine
(100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo,
as double-blind maintenance treatment, for a period of
18 months. Of 349 patients who met screening criteria and
entered the open-label phase, 175 met stabilization criteria
and were randomized to double-blind maintenance treatment
(59 patients with lamotrigine, 46 with lithium and
70 with placebo). Both lamotrigine and lithium were superior
to placebo at prolonging the time-to-intervention for any mood
episode. Lamotrigine was superior to placebo at prolonging the
time-to-a-depressive episode. Lithium was superior to placebo at
prolonging the time-to-a-manic, -hypomanic, or -mixed episode. As a
general conclusion of this study, lamotrigine was effective and
well-tolerated in the long-term maintenance treatment of bipolar
disorder, particularly for prophylaxis of depression.
In summary, lamotrigine can be considered useful in monotherapy or
in combination with other mood stabilizers in bipolar depression
and in rapid cycling bipolar II patients. Preliminary evidence
indicates that it may also be effective in long-term prophylaxis,
particularly preventing depressive episodes. On the other hand,
lamotrigine does not appear to have anti-manic properties.
Oxcarbazepine
The availability of open clinical observations and controlled
studies for oxcarbazepine treatment of bipolar disorder is still
rather limited, but the data currently available seem to be
promising.
Concerning the use of oxcarbazepine in acute mania, the first
controlled, double-blind and cross-over study compared the efficacy
of oxcarbazepine and valproic acid versus placebo in
12 patients with a diagnosis of manic psychosis [114]. The
doses of oxcarbazepine ranged from 1 800 to
2 100 mg/day. All subjects showed a significant
improvement of manic symptoms in comparison with placebo, and a
good tolerability to the treatment. Valproic acid and oxcarbazepine
showed similar efficacy. Another two-week, randomized controlled
study compared the efficacy of oxcarbazepine (dose range
900-1 200 mg/day), and haloperidol (dose range
15-20 mg/day) in 20 patients with acute mania [115]. Both
groups showed a statistically significant improvement in manic
symptoms. These findings prompted the execution of two, two-week,
double-blind, multicentric international studies that compared
oxcarbazepine, lithium, and haloperidol in patients with acute
mania [116]. In the first one (oxcarbazepine versus
haloperidol), 38 manic patients were evaluated. The mean
oxcarbazepine dose was 2 400 mg/day, while the mean
haloperidol dose was 42 mg/day. At the end of the two-week
observation period, both drugs resulted in a statistically
significant improvement in manic symptoms, measured by the
Bech-Rafaelson Mania Scale (BRMS), compared to baseline, with no
significant difference in efficacy between the two groups.
Oxcarbazepine was significantly better tolerated, as the incidence
of side effects was 3.5 times less in the oxcarbazepine group
than among haloperidol-treated subjects. In the second controlled
study (oxcarbazepine versus lithium), 52 manic patients
were evaluated. Mean dosages were 1 400 mg/day for
oxcarbazepine and 1 100 mg/day for lithium. At the end of
the observation period, there was a significant improvement in
manic synptoms compared to baseline, with no significant difference
in efficacy and tolerability between the two groups.
Other studies have evaluated the prophylactic efficacy of oxcarbazepine in preventing bipolar relapses compared with lithium, in two small groups of manic (n = 15) and schizoaffective (n = 15) patients. In one, the authors found that no conclusions about the prophylactic efficacy of oxcarbazepine could be drawn, but treatment with oxcarbazepine at a dose level of 900 mg/day was related to a reduction in the frequency and intensity of manic and depressive episodes similar to that with lithium therapy [117]. Another study found that subjects treated with oxcarbazepine had more frequent relapses than those treated with lithium [118]; it must be noted however, that this study was limited by the fact that some patients treated with oxcarbazepine were non-responders to lithium, and there was a higher dropout rate in the oxcarbazepine group.
Our group [119], conducted a chart review on 48 patients with DSM-IV bipolar I disorder. All patients were resistant or intolerant to standard mood stabilizers. Oxcarbazepine was used either as monotherapy (n = 9), or added to the ongoing treatments (n = 39) with conventional mood stabilizers, antidepressants, and antipsychotics to which patients had not responded after a period of at least 12 weeks. The mean duration of oxcarbazepine treatment was 23.6 weeks (range 4-64), with a mean final dose of 1 218 ± 48 mg/day (range 600-2 400 mg/day). Oxcarbazepine induced an improvement in bipolar symptoms and global functioning in more than 60% of our patients. In particular, the drug seems to be more effective in manic and mixed, than in depressive, symptomatology. In our sample in fact, non-responders showed more frequent depression during the index episode compared to responders. Moreover, two patients interrupted the oxcarbazepine during the observation period due to the reappearance of depression.
In conclusion, knowledge of the mood stabilizing properties of oxcarbazepine is still rather limited. Future placebo-controlled studies are particularly needed to specifically investigate the antidepressant, anti-anxiety and anti-manic properties of oxcarbazepine. Because of its favourable tolerability and drug interaction profile in comparison with other mood stabilizers, oxcarbazepine appears to be a promising agent as an adjunct treatment for those patients who have partial or no response to standard therapeutic regimens.
Gabapentin
A relevant number of case reports and open studies, reviewed by
Carta et al. [120], involving at least 600 patients,
indicate that gabapentin may be effective as an adjunctive
treatment of acute (hypo)mania, and may play an important role in
treatment of refractory bipolar disorder. Available data on the
comparison of gabapentin as a single or adjunct treatment indicate
that it may be efficacious if administered alone, in a subgroup of
bipolar patients with mild or moderate symptoms, whereas it may be
useful in association with standard mood stabilizers in severe
manic or mixed states.
Most studies evaluated the efficacy of gabapentin in acute
treatment of manic or hypomanic episodes [120, 121] and reported
rates of response ranging from 37% to 92%. Several studies
[122-124] suggest that gabapentin may be also useful as an
additional treatment for bipolar mixed states, which have partial
or no response to traditional mood stabilizers. These studies,
however, are conflicting. A study by our group of 21 patients
with bipolar mixed state [123], found that gabapentin has
remarkable efficacy on depressive symptoms, while the effects on
the manic features were limited. However, another study found that
a one-month treatment with gabapentin was useful for both manic and
depressive symptoms [124].
Data on the efficacy of gabapentin in long-term maintenance
treatment are still limited. A recent study by Schaeffer and
Schaeffer [125], re-evaluated the effectiveness in long-term
maintenance treatment in a group of bipolar subjects that were
refractory to traditional mood stabilizers but who had responded to
short-term adjunctive treatment with gabapentin. Thirty-nine
percent of the group had experienced significant benefit from the
adjunctive treatment with gabapentin.
While open studies are in overall agreement about the efficacy of
gabapentin in bipolar spectrum disorders, results from the
controlled studies available tend to contradict these findings
[112, 126]. Frye et al. [112] reported a crossover
comparison of gabapentin, lamotrigine and placebo in
31 bipolar patients who were refractory to standard mood
stabilizers. Single lamotrigine treatment was superior to placebo
(52% of patients who received lamotrigine responded versus 23% of
the placebo group), while there were no significant differences
between gabapentin and placebo. Another study by Pande et
al. [126] found no statistically significant differences
between adjunctive treatment with gabapentin and placebo in
116 patients with resistant bipolar disorder. However, it must
be noted that some methodological limitations in the latter study
may have reduced the validity of the results (reduced compliance,
non-homogeneous composition of the sample, frequent modification of
the associated mood-stabilizer treatments in the placebo group).
Several hypotheses have been developed to explain the controversial
results of the controlled studies. Some authors [126, 127] suggest
that gabapentin may be efficacious on one or more symptom
dimensions that are not adequately catered for by the rating scales
used in controlled studies. In this regard, it must be noted that
gabapentin appears to have also an important anti-anxiety effect,
as indicated by its efficacy in controlled studies on panic
disorder [128] and social phobia [129].
In a recent study [130], we evaluated the predictors of response
for gabapentin as an adjunctive treatment in a sample of
43 subjects with DSM-III-R bipolar disorder, who were
resistant to standard mood stabilizers. Gabapentin was administered
as an adjunctive treatment for an eight-week period, in combination
with other mood stabilizers, benzodiazepines, antidepressants, and
neuroleptics. Eighteen (41.9%) out of 43 patients who began
treatment were considered responders. From our data, gabapentin
seems to have antidepressant and anxiolytic properties. The
improvement in depressive and anxiety symptoms was independent of
the severity of the manic features. On the other hand, manic
symptoms did not show a significant improvement, not even in those
patients where they were the dominant clinical feature.
Other recent studies have reported the efficacy of gabapentin on
major depression in unipolar and bipolar patients [131, 132]. The
observation of a specific efficacy in bipolar patients who have
co-morbid panic disorder or alcohol abuse (and maybe social phobia)
appears to be of great importance. If these findings were to be
confirmed in larger samples, these properties would have great
relevance for clinical practice.
The very favourable pharmacological profile of this drug, in
comparison with traditional mood stabilizers, underscores the great
tolerability and safety of gabapentin as an adjunct treatment for
those patients who have partial or no response to standard
therapeutic regimens.
Topiramate
The use of topiramate in the treatment of bipolar disorder has
been recently reviewed [133]. Initially, topiramate was evaluated
in mood disorders refractory to previous treatments, including the
newer AEDs. Marcotte [134], reviewed charts of 58 consecutive
patients (39 outpatients and 19 inpatients). Forty-four
patients had rapid cycling bipolar disorders characterized by
manic, hypomanic, or mixed episodes; 18 patients had
previously failed to respond to lamotrigine and/or gabapentin in
addition to conventional mood stabilizers. The mean duration of
topiramate treatment was 16.0 weeks and the mean dose level
approximately 200 mg/day. Thirty-six (62%) out of the
58 patients exhibited marked or moderate improvement. Adverse
events were predominantly related to the gastrointestinal tract
(i.e., nausea, and diarrhoea) and central nervous system (i.e.,
paresthesias, somnolence, fatigue, impaired concentration and
memory). Chengappa et al. [135] reported data on
20 patients, 18 with DSM-IV bipolar I disorder and two
subjects with resistant schizoaffective disorder bipolar type.
Topiramate was started at 25 mg/day and increased by
25-50 mg every three-seven days up to a target dose of between
100 and 300 mg/day, as other medications were held constant
for five weeks. By week five, 12 (60%) subjects were responders;
all patients lost weight with a mean loss of 9.4 lb in
5 weeks, with a significant reduction in body mass index
(BMI). McElroy et al. [136] evaluated the response of
56 bipolar outpatients who had been treated with adjunctive
topiramate in an open-label, naturalistic fashion. Of the
54 patients who completed at least two weeks of treatment,
30 had manic, mixed, or cycling symptoms, 11 had
depressed symptoms, and 13 were relatively euthymic at the
time topiramate was begun. Patients who had been initially treated
for manic symptoms displayed significant reductions in standard
ratings scores after four weeks, after 10 weeks, and at the
last evaluation. Those patients who were initially depressed or
treated while euthymic showed no significant changes. Patients as a
group displayed significant decreases in weight and body mass index
from topiramate initiation to week four, to week 10, and to the
last evaluation. The effect of adjunctive topiramate was also
evaluated in 11 patients in an on-off study design [137].
Topiramate was added after stable plasma levels of concomitant mood
stabilizers had been reached, and was titrated within one week to a
final dose range of 25 to 200 mg/day. Topiramate was
discontinued after 10 days, while concomitant medication
remained unchanged. After five days, topiramate was reintroduced at
similar or increased dosages for another seven days. Seven of the
11 patients initially showed a good response
with > 50% reduction in Young Mania Rating Scale
(YMRS) score. One patient showed psychotic features following a
rapid increase in topiramate dosage and dropped out on day 10.
After discontinuation of topiramate, seven of the remaining
10 patients worsened, two remained stable, and one
discontinued follow-up after good recovery. After reintroducing
topiramate, all patients improved again within a week. With the
exception of the patient who developed psychosis, topiramate was
well tolerated and did not interfere with plasma levels of
concomitant medication, except for the level of carbamazepine in
one patient.
The employment of topiramate as a monotherapy (dose range
50-1 600 mg/day) was firstly evaluated by Calabrese et
al. [138], who conducted an open study on ten manic inpatients.
After a mean period of 16 days (maximum 28 days), three
patients showed a marked improvement, one moderate, four minimal or
absent and two patients were judged worsened; the drug appeared to
be well tolerated. Ghaemi et al. [139] in a retrospective
study reported on 76 patients with bipolar spectrum disorders
that were treated with topiramate. Results showed that 47% of
subjects (n = 36) had a “mild” improvement, 13%
(n = 10) a “moderate” or “marked” improvement; 50%
of the sample subjects showed a weight loss, the size of which was
directly related to the dosage of topiramate. Most frequently
reported side effects, in addition to weight loss, were cognitive
difficulties, sedation, paresthesia nausea, insomnia, and
headache.
As regard treatment-resistant bipolar patients, Guille and Sachs
[140] reported data on 14 patients attending a bipolar clinic
who were treated with topiramate for an average of 22.4 weeks.
Nine of these patients (64%) experienced an increased level of
functioning and a decrease in symptom severity during treatment
with adjunctive topiramate. Eleven patients remained on treatment
for longer than two weeks. Eight patients (73%) experienced a
significant improvement in their co-morbid conditions.
McIntyre et al. [141] evaluated the efficacy and
tolerability of topiramate and bupropion SR, when added to mood
stabilizer under single-blind conditions (rater-blinded), in
patients meeting DSM-IV criteria for bipolar I and II depression. A
total of 36 out-patients with HDRS scores = 16 were
randomized to receive escalating doses of either topiramate
(50-300 mg/day) or bupropion SR (100-400 mg/day) for
eight weeks. A significant and comparable reduction in depressive
symptoms was observed from baseline to endpoint following
topiramate (56%) and bupropion SR (59%) treatment. Both topiramate
and bupropion SR were generally well-tolerated; 13 patients
discontinued the study: two because of lack of efficacy, one due to
withdrawal of consent and 10 following side-effects (six in
the topiramate and four in the bupropion SR-treated group).
Topiramate produced greater weight loss
(mean = 5.8 kg) than bupropion
(mean = 1.2 kg). These preliminary data suggest that
adjunctive topiramate may reduce depressive symptom severity in
acute bipolar depression.
The preliminary results concerning the use of topiramate in
bipolar disorder appear promising, especially for adjunctive
treatment for patients who are non-responders to other mood
stabilizers. The appetite-reducing effect of the drug, which was
remarkably demonstrated in the various studies, has interesting
prospects for the treatment of the patients with bipolar disorder
and co-morbid bulimia nervosa, binge-eating disorder or obesity.
The antidepressant efficacy of this compound requires confirmation
via double-blind, placebo-controlled studies. In addition,
topiramate offers a favourable side-effect profile, which includes
decreased appetite and weight loss in some patients.
Tiagabine and zonisamide
Tiagabine and zonisamide have only been evaluated in few, small, open case-series. Initially, a 14-day open trial with tiagabine was conducted in eight acutely manic inpatients with DSM-IV bipolar I disorder, two of them as monotherapy and six as an add-on to previously insufficient mood-stabilizing medications [142]. None of the patients showed clear-cut relief from manic symptoms during the two-week observation period. Subsequently, Schaffer et al. [143] treated in an open fashion with adjunctive tiagabine at a low-dose range (1-8 mg/day), 22, adult, bipolar outpatients, who were considered unsatisfactory responders to standard medications. After six months, eight (36%) of the patients were considered responders. All 14 non-responders had to discontinue tiagabine because of unacceptable, but reversible, side effects; one non-responder experienced breakthrough absence seizures. Finally, 17 treatment-refractory patients participating in the Stanley Foundation Bipolar Network long-term follow-up study were offered open treatment with add-on tiagabine [144]. Four patients discontinued low-dose tiagabine prior to the second visit and were excluded from data analysis; 13 patients received a mean of 38 days of treatment at a mean dose of 8.7 mg/day of tiagabine. Only three (23%) patients showed noticeable or very noticeable improvement, and 10 (77%) patients showed no change, or worsening. Significant adverse events were noted, including two presumed seizures.
Available evidence appears to indicate a limited efficacy of tiagabine for acute mania. Moreover, an unfavorable side-effects profile is reported, in particular at high doses. At the moment, tiagabine cannot be recommended for use in patients with bipolar disorder.
The effect of adjunctive zonisamide (100-600 mg/day) was examined in 24 patients (15 bipolar manic, six schizoaffective manic, and three excited schizophrenic) [145]. Approximately 71% of all the patients and 80% of the bipolar group had more than a moderate global improvement; 25% of all the patients and 33% of the bipolar manic patients showed remarkable global improvement. No serious adverse reactions were found and no patients required zonisamide withdrawal. One patient developed both leukocytosis and mildly abnormal liver function tests. One developed leukocytosis and another reported mild sleepiness. These reactions disappeared when zonisamide was discontinued. Further controlled studies are necessary in order to confirm a possible role for zonisamide in the treatment of bipolar disorder.
Other psychiatric disorders
AEDs have been utilized in a variety of other psychiatric conditions characterized by “atypical” anxiety, impulsivity and aggressive behaviour. Preliminary evidence exists also for atypical psychosis, and eating and personality disorders [146, 147]. Most information in this widening spectrum of indications is based on case series, open studies and small controlled trials and it should be considered preliminary.
Conclusions
In addition to their use for the management of epilepsy, some traditional and newer AEDs may represent the treatment of choice, or a valuable alternative to standard treatments, in a variety of nonepileptic neurological and psychiatric conditions, including trigeminal neuralgia, neuropathic pain, migraine prophylaxis, essential tremor and bipolar disorder. However, evidence for the efficacy and safety of AEDs, especially the newer compounds, for many of these disorders is still inadequate. Therefore, there is an ongoing need for controlled studies with a large number of patients and greater homogeneity of diagnosis in order to establish the efficacy of individual AEDs in the management of clinical conditions other than epilepsy. Finally, when considering the use of AEDs for nonepileptic indications, their safety profile must be weighed against their reported efficacy. In this respect, newer (AEDs) appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, with subsequent advantages in terms of compliance with treatment [148]. n