Антиконвульсанты при тревожных расстройствах

Can Anticonvulsants Help Patients With Anxiety Disorders?

Evidence supporting antiepileptics for mood disorders and schizophrenia

Medication	Bipolar disorder			Major depressive disorder	Schizophrenia
	Mania	Depression	Maintenance
Carbamazepine					(aggression, impulsivity)
Lamotrigine					(adjunct to clozapine)
Valproate					(aggression, impulsivity)
Gabapentin
Levetiracetam
Oxcarbazepine
Tiagabine
Topiramate
Zonisamide
	: strong evidence supporting efficacy;
	: moderate evidence supporting efficacy;
	: weak evidence supporting efficacy
Source: For an extensive bibliography of studies that support these recommendations, see this article at CurrentPsychiatry.com

Table 2
Off-label use of antiepileptics for various psychiatric disorders

Condition/disorder	Possible medication(s)*
Alcohol withdrawal/relapse prevention	Carbamazepine, topiramate, valproate
Benzodiazepine withdrawal	Carbamazepine, valproate
Binge eating disorder	Topiramate, zonisamide
Bulimia nervosa	Topiramate
Drug dependence/abstinence	Carbamazepine, lamotrigine, topiramate, tiagabine
Generalized anxiety disorder	Pregabalin, tiagabine
Obesity	Lamotrigine, topiramate, zonisamide
Panic disorder	Valproate
Posttraumatic stress disorder	Lamotrigine
Social phobia	Gabapentin, pregabalin
* Based on small randomized controlled trials, open-label trials, or case reports. Further investigation in large systematic trials is needed

Explain to patients taking topiramate or zonisamide that increasing their fluid intake will significantly reduce kidney stone risk

The FDA recently announced a warning of a risk of aseptic meningitis with lamotrigine.11 In 40 reported cases, symptoms—headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia, and myalgias—occurred between 1 and 42 days of treatment and typically resolved after lamotrigine was withdrawn. In 15 patients in whom lamotrigine was re-initiated, meningitis symptoms returned quickly and with greater severity.

Antiepileptics for psychiatric illness: Find the right match

Детский аутизм и эпилепсия

Medscape: What is the risk for epilepsy in autism?

Dr. Chez: The risk for epilepsy in autism is 10%-30%, and it usually develops in the teenage or early adult years. Children with autism who are lower functioning, with mental retardation and cerebral palsy, for example, are more likely to develop epilepsy.

In addition, there are many children with autism who demonstrate epileptic spikes when monitored on 24-hour electroencephalography, but who do not manifest clinical epileptic seizures. These may be worth treating with antiepileptic drugs, as treatment may lead to improved behavior and receptive language. If the spikes are in the central temporal region, affecting the language area, I will usually try a trial of valproic acid. Valproic acid may also act as a mood stabilizer in these children, and also inhibits interleukin 1 cytokines, which may provide additional benefit. Other antiepileptic drugs may also be effective, although I have not seen good results with carbamazepine. There is also anecdotal evidence of improvement with the ketogenic diet.

Dr. Pellock: This is a controversial area. There are a few cases where treatment of epileptic spikes has resulted in improved behavior. However, without a clear manifestation of seizures, it is frequently difficult to know whether the short and long-term risks of the medications are really warranted. Clear goals need to be established to determine whether the treatment benefits the child. As a routine, I do not treat isolated spikes on the electroencephalogram, just as I would not treat isolated spikes in any child, with or without autism.

An Update on Autism -- Perspectives and Treatment: Autism and Epilepsy

Роль L-метилфолата в терапии депрессивных расстройств

Folate is a water soluble B vitamin (B9), considered one of the 13 essential vitamins. The primary function of folate is the transfer of methyl and formyl groups, thus, it is essential for cell growth and reproduction, the breakdown and utilization of proteins, the formation of nucleic acids, red blood cell maturation, and a variety of CNS reactions. Dihydrofolate is the dietary form found in orange juice, spinach, asparagus, beans, liver, yeast, whole grain cereals, and eggs. Folic acid is the synthetic form of folate in over-the-counter vitamins and used to fortify the food supply (to help prevent neural tube defects, the FDA mandated folic acid fortification of flour in 1998). Folic acid is also the predominant form used in prescription strength prenatal vitamins. Both folic acid and dihydrofolate are not biologically active forms of folate, but are essentially pro-drugs, and must undergo enzymatic transformation to L-methylfolate in order to be used by cells, and unlike other forms of folate, L-methylfolate readily crosses the blood-brain barrier for use in the CNS.


Almost 85% of dietary folate and nearly all supplemental folic acid is absorbed into the venous system in the proximal small intestine. The enzymatic conversion begins in the intestinal wall—it is a three step process for dihydrofolate, and a four step process for folic acid (Slide 3). Folic acid is converted to dihydrofolate (DHF) by dihydrofolate reductase enzyme (DHFR), and DHF is then converted to tetrahydrofolate (THF). The conversion of THF to 5,10-methyleneTHF follows. Finally, the conversion of 5,10-methyleneTHF to L-methylfolate is achieved by the methyltetrahydrofolate reductase enzyme (MTHFR). This last step completes the four step transformation process by which the bioactive cofactor, L-methylfolate, is made available to the brain to be used in the synthesis of monoamine neurotransmitters associated with mood regulation (serotonin, norepinephrine, and dopamine).

There are five trials that examine folate therapy in depressive disorders. In a study59 with patients who had low or borderline low RBC folate, depressed patients on tricyclic antidepressants or MAOIs were augmented with methylfolate 15 mg (L-methylfolate 7.5 mg) experienced significantly greater clinical improvement and social improvement at 3 months (P<.02) and 6 months (P<.01) compared to patients treated with antidepressants alone. The methylfolate-augmented patients continued to improve for 6 months compared to patients augmented with placebo, and none experienced relapse. In a separate double-blind, controlled trial60 comparing methylfolate 50 mg/day to trazodone 100 mg/day, depressed patients experienced a significant decrease in HAM-D scores at 4 and 8 weeks in both groups, with response rates in the methylfolate group at 45%, and in the trazodone group (not statistically significant) at 29%.


An open label trial61 of methylfolate as monotherapy in elderly depressed subjects demonstrated an 81% response rate (>50% reduction in HAM-D) by 6 weeks of therapy. A second monotherapy study examined a depressed population of 36 chronic alcoholics. After a week of placebo wash-out, subjects received 4 weeks of 90 mg methylfolate therapy. This dosing (30 mg TID) significantly improved depressive symptoms based on the HAM-D scale with the majority reporting improved mood and less fatigue (P<.01).62 Alpert and colleagues63 conducted an open label trial augmenting selective serotonin reuptake inhibitor (SSRIs) with folinic acid in patients who had failed at least 4 weeks of SSRI therapy. The response to folinic acid was not robust (P<.01, n=22), but it was well tolerated overall.

The standard dose of L-methylfolate for the augmentation of antidepressants is one 7.5 mg tablet/day. No titration is necessary, and it is not associated with withdrawal symptoms at discontinuation. The maximum amount of L-methylfolate that can be absorbed in one dose is ~15 mg.67 If more than one 7.5 mg tablet/day is needed, it may be prudent to give in divided doses. All reported adverse events occur at placebo rates or lower, and overall it is an extremely well tolerated agent, allowing patients to continue L-methylfolate therapy as long as necessary to maintain remission. There are no known contraindications and no known drug interactions.

The Role of L-methylfolate in Depressive Disorders

Прегабалин при ГТР

"These results indicate that pregabalin is an effective, rapidly acting, and safe treatment for generalized anxiety disorder. In short-term treatment, pregabalin does not appear to have the withdrawal symptoms associated with the benzodiazepines."

Pregabalin in Generalized Anxiety Disorder: A Placebo-Controlled Trial

"The dose of 150 mg pregabalin over the four weeks of the trials was found insufficient for the treatment of GAD. In the dose range of 200-450 mg daily, a clinically significant effect was obtained, although with a plateau-like curve which was not increased for the maximum dose of 600 mg daily."

Dose-response relationship of pregabalin in patients with generalized anxiety disorder. A pooled analysis of four placebo-controlled trials.

"The efficacy of pregabalin in treating GAD is not surprising as a number of other antiepileptic drugs have also been shown to have anxiolytic properties and to be effective in treating patients with anxiety disorders. Valproate has been shown to have efficacy in the treatment of panic disorder (Primeau et al 1990; Woodman and Noyes 1994; Baetz and Bowen 1998) and blocks lactate-induced panic attacks (Keck et al 1993). The antiepileptic drug carbamazepine has efficacy in the treatment of panic disorder (Tondo et al 1989), post-traumatic stress disorder (PTSD) (Lipper et al 1986), and obsessive compulsive disorder (OCD) (Joffe and Swinson 1987). Lamotrigine is potentially effective in the treatment of PTSD (Hertzberg et al 1999) and may have an adjunctive role in the treatment of refractive OCD (Kumar and Khanna 2000). Topiramate has been shown to be efficacious in open-label trials for PTSD (Berlant and van Kammen 2002; Berlant 2004), social phobia disorder (Van Ameringen et al 2004) and may have an adjunctive role in treatment-resistant OCD (Van Ameringen et al 2006). However, unlike previous antiepileptic drugs which primarily block sodium and potassium channels or increase cerebral GABA concentrations, pregabalin decreases presynaptic calcium currents and in doing so decreases the release of several neurotransmitters, including glutamate (Dooley et al 2000a), substance P (Fehenbacher et al 2003), calcitonin-gene-related peptide (Fehenbacher et al 2003), and norepinephrine (Dooley et al 2002). Interestingly, many of these neurotransmitters have been implicated in the pathogenesis GAD or other anxiety disorders (Erikkson et al 1991; Geracioti et al 2001; Olsson et al 2004; Geracioti et al 2006). As might be expected, agents that pharmacologically dampen these systems have therapeutic roles in a number of anxiety disorders (Peet and Ali 1986; Furmark et al 2005; Strawn and Geracioti 2006). Also, decreases in the activity of these or related “fear circuits” that underlie the pathophysiology of certain anxiety disorders (Stahl 2004) could explain the efficacy of pregabalin in patients with GAD. It will be of interest to examine the effects of pregabalin in other anxiety disorders such as PTSD, panic disorder, or even meal-related anxiety in anorexia nervosa (wherein additional benefit may be conferred by pregabalin-associated weight gain)."

The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic

Антиконвульсанты в терапии поведенческих и психологических симптомов деменции

"INTRODUCTION: Dementia, besides the dominant cognitive disorders that define it, is associated with behavioral disturbances, the consequences of which are, on various levels, a determining factor for the handling of these patients. The treatment of behavioral and psychological symptoms is essential and although, to date, no therapeutic solution is satisfactory, it is necessary to look for an alternative to the neuroleptics usually employed, which raise real problems of tolerance in this geriatric population. BACKGROUND: For several years, anticonvulsants, among which some have shown mood stabilizing activity, have been the object of research in this indication. The purpose of this review of the literature is to assess the interest and the limits of anticonvulsant mood stabilizers (carbamazepine, valproic acid, gabapentin, lamotrigine, topiramate, oxcarbazepine) in the treatment of the so-called "noncognitive" symptoms of dementia. Their mechanism of action in mood disorders is not well known, but it would appear to be via the modulation of glutamate-mediated excitatory synaptic transmission and gamma-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission that anticonvulsants might reduce behavioral symptoms in demented patients. METHODS: The method employed in this work was a systematic bibliographic review, in which only the double-blind placebo-controlled studies or the clinically detailed enough open-labelled studies using validated scales were retained. RESULTS: Among these medications, only carbamazepine demonstrated its efficacy in behavioral and psychological symptoms of dementia (BPSD) in controlled studies, notably that of Tariot et al. [J Am Geriatr Soc 42 (1994) 1160-1166 and Am J Psychiatry 155 (1998) 54-61] and Olin et al. [Am J Geriatr Psychiatry 9 (2001) 400-405], but with significant adverse events (sedation, hyponatremia, cardiac toxicity), particularly in the elderly and, being a strong enzymatic inducer, with a high likelihood of drug-drug interactions. Valproic acid showed some interesting results in BPSD within a large number of open studies and case reports. However, among the five controlled studies that have been published [Curr Ther Res 62 (2001) 51-67; Am J Geriatr Psychiatry 9 (2001) 58-66; Int J Geriatr Psychiatry 17 (2002) 579-585; Curr Alzheimer Res 2 (2005) 553-558 and Am J Geraitr Psychiatry 13 (2005) 942-945], none confirmed its efficacy on these symptoms. Regarding its tolerability in the geriatric population, no notable major side effect was reported (haematologic and hepatic effects are not more frequent than in the general population), except possible excessive sedation. Moreover, it appears that valproic acid could have neuroprotective effects, even if the contrary has been observed in a recent study. More studies need to be (and are being) conducted, notably on the interest of valproic acid in prophylaxis of BPSD. Gabapentin seems to be worthwhile and well tolerated in this indication, but no controlled study has been conducted to prove its efficacy, even if a quite important number of case reports and open studies have shown encouraging results. Concerning lamotrigine, which may potentially induce severe cutaneous side effects when administered with valproic acid, this drug has shown its efficacy in bipolar disorders and two recent case reports seem to indicate some interest in BPSD. Furthermore, lamotrigine appears to have neuroprotective effects. Although topiramate has shown interesting results in one open study in BPSD, its use in demented patients cannot be recommended because of its deleterious effect on cognitive functions. Oxcarbazepine, theoretically, could be an alternative to carbamazepine, which is, as aforesaid, the only anticonvulsant that proved its interest in BPSD. However, no clinical study has yet been published to support this hypothesis. This drug is better tolerated than carbamazepine, but induces severe and more frequent hyponatremia. DISCUSSION AND CONCLUSION: Finally, although we all know that antipsychotics should no longer be prescribed in the elderly, the treatment of behavioral and psychological symptoms of dementia remains a difficult problem, considering the lack of a real alternative to these medications. Anticonvulsant mood stabilizers are an interesting solution but none of them, other than carbamazepine, which did, but which is not better tolerated than the usual drugs in this population - was able to prove its efficacy in this indication. Among these medications, valproic acid, gabapentin and lamotrigine should be studied further, and the neuroprotective effect of some of them is an interesting route for research."

Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD)

Кататония - обзор

http://www.psyobsor.org/1998/35/3-4.html

Сравнение окскарбазепина и карбамазепина в терапии аффективных расстройств

In summary, the patient charts reviewed demonstrated that carbamazepine, as well as, oxcarbazepine are equally effective and tolerable as mood stabilizers.
Effectiveness and Tolerability of Carbamazepine vs. Oxcarbazepine as Mood Stabilizers

эндокринные эффекты нормотимиков

Both seizures and antiepileptic drugs may induce disturbances in hormonal system. Regarding endocrine effects of anticonvulsants, an interaction of these drugs with gonadal, thyroid, and adrenal axis deserves attention. Since majority of antiepileptic drugs block voltage dependent sodium and calcium channels, enhance GABAergic transmission and/or antagonize glutamate receptors, one may expect that similar neurochemical mechanisms are engaged in the interaction of these drugs with synthesis of hypothalamic neurohormones such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH). Moreover some antiepileptic drugs may affect hormone metabolism via inhibiting or stimulating cytochrome P-450 iso-enzymes. An influence of antiepileptic drugs on hypothalamic-pituitary-gonadal axis appears to be sex-dependent. In males, valproate decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but elevated dehydroepiandrosterone sulfate (DHEAS) concentrations. Carbamazepine decreased testosterone/sex-hormone binding globulin (SHBG) ratio, whereas its active metabolite--oxcarbazepine--had no effect on androgens. In females, valproate decreased FSH-stimulated estradiol release and enhanced testosterone level. On the other hand, carbamazepine decreased testosterone level but enhanced SHBG concentration. It has been reported that carbamazepine, oxcarbazepine or joined administration of carbamazepine and valproate decrease thyroxine (T4) level in patients with no effect on thyrotropin (TSH). While valproate itself has no effect on T4, phenytoin, phenobarbital and primidone, as metabolic enzyme inducers, can decrease the level of free and bound thyroxine. On the other hand, new antiepileptics such as levetiracetam, tiagabine, vigabatrine or lamotrigine had no effect on thyroid hormones. With respect to hormonal regulation of metabolic processes, valproate was reported to enhance leptin and insulin blood level and increased body weight, whereas topiramate showed an opposite effect. In contrast to thyroid and gonadal hormones, only a few data concern antiepileptic drug action in HPA axis. To this end, no effect of antiepileptic drugs on adrenocorticotropic hormone (ACTH)/cortisol circadian rhytmicity was found. Valproate decreased CRH release in rats, whereas lamotrigine stabilized ACTH/cortisol secretion. Moreover, felbamate was found to inhibit stress-induced corticosterone release in mice. Interestingly, recent data suggest that felbamat and some other new antiepileptic drugs may inhibit transcriptional activity of glucocorticoid receptors. Summing up, the above data suggest that traditional antiepileptic drugs may cause endocrine disturbances, especially in gonadal hormones.
Endocrine effects of antiepileptic drugs

+ Effects of antiepileptic drugs on immune system