Противосудорожный препарат ламотригин может дать начало новому классу антибиотиков — ингибиторам сборки бактериальных рибосом

В связи с растущей проблемой антибиотикорезистентнтности активно ведутся поиски новых антибактериальных препаратов, действующих как уже на известные «мишени», так на структуры бактериальной клетки, ранее не являвшиеся мишенью действия антибиотиков. Причём если ранее в основном пытались ингибировать важнейшие процессы жизнедеятельности микроорганизмов, то сейчас рассматриваются и варианты воздействия на построение (сборку) отдельных структур микробной клетки.

Исследователями был проведён скрининг большого числа уже применяющихся в клинической практике лекарственных средств на наличие зависимой от температуры способности ингибировать рост Escherichia coli. Одним из препаратов, активность которого наиболее выраженно уменьшалась при снижении температуры, был давно применяющийся противосудорожный препарат ламотригин. В присутствии ламотригина в микробных клетках быстро возрастала концентрация незрелых 30S и 50S субъединиц рибосом. При этом препарат не нарушал процесс трансляции и непосредственно не влиял на синтез белков in vitro и in vivo. Таким образом, ламотригин может стать первым представителем целого нового класса антибактериальных препаратов — ингибиторов сборки бактериальных рибосом.

Однако, несмотря на очевидную перспективность разработки антибиотиков с новыми механизмами действия, вероятность развития к ним устойчивости также возможна. В частности, ряд спонтанных мутаций в домене II фактора инициации трансляции IF2 блокируют присоединение ламотригина к IF2 и, соответственно, нивелируют активность данного препарата в отношении процесса сборки бактериальных рибосом.

 Противосудорожный препарат ламотригин может дать начало новому классу антибиотиков — ингибиторам сборки бактериальных рибосом

Оланзапин превзошел ламотриджин в профилактике депрессивной фазы биполярного аффективного расстройства

Background

Bipolar disorder is a highly recurrent disease and has great impact on the function of patients. Depressive symptoms consist of more than 50% of life time during the illness and may lead to self harm or suicidal behaviors. Little is known about the antidepressant effects of olanzapine, an atypical antipsychotic, as monotherapy despite its indication for preventing manic episodes. In contrast, lamotrigine, a mood stabilizer, has been proven to be effective in preventing depression in patients with bipolar disorder. However, no studies have compared the efficacy between lamotrigine and olanzapine in the maintenance treatment of bipolar disorder. This enriched naturalistic study was implemented to assess the effectiveness of olanzapine and lamotrigine as monotherapy in the prevention of recurrence of bipolar disorder.

Methods

Patients with bipolar disorder in a euthymic state (Young's Mania Rating Scale (YMRS) score < 12, and 21-item Hamilton Depression Rating Scale (HAM-D) score < 7) for at least two months, having already received either olanzapine or lamotrigine as the maintenance treatment were recruited. The patients maintained with olanzapine (n = 22) were applied to olanzapine group whereas those maintained with lamotrigine (n = 29) were applied to lamotrigine group. They were followed up for 12 months. Differences in the efficacy between olanzapine and lamotrigine in recurrence prevention were analyzed. The Kaplan-Meier method was used to generate time-to-recurrence curves, and differences between the two groups were compared using the log-rank test.

Results

Olanzapine had a significantly lower recurrence rate of depressive episodes than lamotrigine (20.0% vs. 57.7%, chi2 = 6.62, p = .010). However, olanzapine and lamotrigine had similar mania (15.0% vs. 0%, chi2 = 4.17, p = .075, Fisher's exact test) and any mood episode (35.0% vs. 57.7%, chi2 = 2.33, p = .127) recurrence rates. Olanzapine was significantly superior to lamotrigine in the time to recurrence of depressive episodes (chi2 = 4.55, df = 1, p = .033), but there was no difference in the time to recurrence of any mood episode (chi2 = 1.68, df = 1, p = .195).

Conclusions

This prospective naturalistic study suggests that olanzapine is more effective than lamotrigine in the prevention of depressive episodes in patients with bipolar disorder. Future large-scale randomized studies are warranted to validate our results.

 Olanzapine is superior to lamotrigine in the prevention of bipolar depression: a naturalistic observational study

Ламотриджин при униполярной депрессии

On the basis of currently available evidence, clinicians are urged to not prescribe lamotrigine for MDD. If a detailed and thorough clinical evaluation finds no specific evidence of bipolar disorder (mania or hypo­mania) in a particular patient, it is not appropriate to prescribe lamotrigine for that patient, since there is no evidence that that particular patient has bipolar disorder.

 Lamotrigine for Major Depressive Disorder Is Inappropriate

Стратегии потенцирования действия клозапина

Background. When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder.

Methods. Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g). Results. Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal.

Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.

Conclusions. Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

 Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review

Отсутствие эффективности в РКИ: зипрасидон при биполярной депрессии и ламотриджин при депрессии

Both bipolar depression and refractory unipolar depression are highly difficult to treat. Because few randomized controlled trials (RCTs) address these conditions, clinicians often try medications either from the same class as proven-effective agents or that are effective for related conditions. These two large, well-conducted RCTs remind us that such clinical strategies may be neither sound nor effective.

What Lamotrigine and Ziprasidone Are Not Good For 

Метиленовый синий как нормотимик

The investigators administered methylene blue to 37 subjects meeting criteria for bipolar disorder, while maintaining lamotrigine(Drug information on lamotrigine) as their primary mood stabilizer. Patients were randomized to receive 13 weeks treatment with either 195 mg methylene blue daily, or 15 mg as a putative subtherapeutic dose in lieu of a placebo that mimics the color in urine; with groups switching the regimen for an additional 13 weeks.

Alda reported that the active dose was associated with statistically significantly improved mood symptom scores from baseline on multiple measures, including the Montgomery-Asberg Depression Rating Scale (MADRS). There was no therapeutic effect apparent on cognitive performance, but no decrement observed with its use.

Methylene Blue Studied for Bipolar as FDA Issues Warning

Антиконвульсанты при тревожных расстройствах

Can Anticonvulsants Help Patients With Anxiety Disorders?

Маниакальная симптоматика ассоциированная с приступами мигрени

This is a case report of a previously diagnosed "treatment-refractory bipolar" patient whose successful treatment of atypical migraine resulted in the questioning of any psychiatric diagnosis.

A 47-year-old man was referred to the Mood Disorders Clinic for severe migraine associated with mood, "psychic," and neurologic symptoms. He had first presented to Psychiatry 8 years earlier, for acute "mania" with agitation, extreme lability, intense anger, and religiosity necessitating hospitalization. Subsequently, he had recurrences of similar manic "crises" followed by a "depressive" states consisting of cognitive dysfunction, avolition, and anhedonia. He also experienced severe headache and nonspecific neurological symptoms. A diagnosis of migraine was suspected, and a thorough neurological work-up did not yield other diagnoses. Medical history revealed multiple recurrent migraine-equivalents since childhood (particularly, abdominal pain).

Each psychiatric "crisis" was preceded by weeks of increasingly frequent, severe, early morning migraine attacks, with subsequent sleep deprivation, and intensification of migraine symptoms, including aura, with disorganized speech and thinking and bizarre behavior. A prolonged period of complete rest would break the cycle of migraine, accompanied by complete resolution of psychiatric symptoms.

Previous treatments included lithium, buproprion, as well as nortriptyline, stemetil, valproic acid, and quetiapine, none of which were helpful. Family history was positive for migraine and negative for psychiatric disorders. On referral, his medications were propranolol 40 mg twice daily, valproic acid 500 mg twice daily, and lamotrigine 100 mg twice daily. Valproic acid level was therapeutic. A diagnosis of mood disorder, bipolar type secondary to severe migraine was made.

Discussion

This case illustrates the importance of inquiry of neurological symptoms, in particular headache, in patients with bipolar disorder. Patients with bipolar disorder have a greater-than-twofold risk of having migraine, as compared with the general population.1 Treatment for migraine, irrespective of mood disorder, includes amitriptyline, valproate, topiramate, and beta-blockers.2 In patients with bipolar disorder and migraine, judicious use of treatments for both disorders should be considered. Lamotrigine was used for this patient because valproate, although approved for both disorders,3 did not ameliorate the migraine symptoms. For bipolar disorder, lamotrigine is efficacious in the prevention of depressive episodes and, possibly, rapid-cycling type.4 Less evidence supports its use in acute depression or mania.4 For migraine, lamotrigine was not beneficial in a placebo-controlled trial, but had some effectiveness in two open pilot studies for the treatment and prevention of migraine aura.2

Lamotrigine is generally well tolerated, with an acceptable side-effects profile (mainly dizziness, nausea, and insomnia), and may be considered for a patient with aura nonresponsive to other medication. Slow and low dose increase is recommended for side-effects monitoring, especially for severe rashes and Steven's Johnson syndrome. In our patient, lamotrigine was increased to 200 mg twice daily. Use of lamotrigine with valproate may increase lamotrigine concentrations by up to 200% because of increased lamotrigine clearance inhibition,3,5 and valproate levels may also decrease.3 The patient's headache duration eventually decreased to 1 hour nightly, and he returned to work full-time with a 45-minute nap.

Atypical Migraine Manifesting as Mania

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

Потенциирование клозапина: сульпирид, амисульприд, ламотриджин

A frequent treatment strategy for clozapine-resistant patients with schizophrenia is the use of specific augmentors that are suitable for adjunctive therapy. Clozapine is a polyvalent drug but it lacks high-potency dopamine receptor blockade (Kerwin & Osborne, 2000). Therefore, there has been interest in using as augmentors substituted benzamides with highly selective dopamine receptor blocking profiles (Kerwin, 2000). Augmentation strategies incorporating sulpiride are well documented. The authors of one study of sulpiride augmentation in 28 patients partially responsive to clozapine (Shiloh et al, 1997) noted a mean reduction of about 40–50% in various clinical response scores (Brief Psychiatric Rating Scale and Scale for the Assessment of Positive Symptoms).

Several groups have been interested in mimicking this study with amisulpride, a relative of sulpiride that is even more selective at the dopamine D2 receptor. A case series by Zink et al(2004) showed improvement in previously treatment-resistant symptoms following a combined treatment strategy of clozapine and amisulpride. In addition, our group performed an open trial of amisulpride augmentation in a long-term (52 weeks) study. Significant improvement was observed in half of the patients, with no additional side-effects. Moreover, this study monitored plasma levels to determine whether this was a pharmacokinetic interaction. Clozapine levels did not change throughout the duration of the trial, suggesting a pharmacodynamic interaction (Munro et al, 2004).

Augmentation with anti-epileptics
A glutamate hyperfunction hypothesis of schizophrenia has generated interest in the role of glutamate release inhibitors as clozapine augmentors. In a study of 26 treatment-resistant patients receiving lamotrigine (17) or topirimate (9) in addition to their existing antipsychotic treatment (a variety of antipsychotics), a significant improvement was observed when lamotrigine was added to risperidone, haloperidol, olanzapine or flupenthixol. However, no significant effect was observed in patients receiving topirimate augmentation in addition to clozapine, olanzapine, haloperidol or flupenthixol (Dursun & Deakin, 2001). The therapeutic effects of lamotrigine augmentation were also assessed in a rigorous randomised placebo-controlled cross-over study of 34 clozapine-resistant patients (Tiihonen et al, 2003). In this 14-week study, lamotrigine treatment significantly improved positive symptoms and general psychopathological symptoms, but had no effect on negative symptoms. The authors suggested that this was the first time a non-dopamine antagonist had proven efficacy in schizophrenia, giving further credence to the hyperglutamate neurotransmission hypothesis for the generation of positive symptoms in the disorder.

Management of clozapine-resistant schizophrenia

Глутаматергические механизмы ОКР

Glutamatergic Dysfunction in Obsessive-Compulsive Disorder and the Potential Clinical Utility of Glutamate-Modulating Agents

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

Ламотриджин и ЭСТ

OBJECTIVE:: To evaluate the effect of lamotrigine (LMT) on electroconvulsive therapy (ECT)-induced seizures. METHODS:: Charts of all patients receiving LMT while undergoing an ECT course from July 2001 through May 2009 were reviewed. Apart from demographic variables, data collection consisted of diagnosis, indication for ECT, index or continuation ECT, electrode placement, stimulus dose, motor and electroencephalographic seizure duration, LMT dose, and number of restimulations. The stimulus dose and the seizure duration of ECT treatments with concurrent LMT (>/=200 mg/d) were compared with the stimulus dose and seizure duration of ECT treatments without concurrent LMT. RESULTS:: Lamotrigine was used by 19 patients (16 women, 3 men) during 289 treatment sessions. Eleven patients had ECT treatments with and without LMT, of which 8 were at a dosage of 200 mg/d or higher. Analyses did not reveal a significant difference in seizure duration and stimulus dose. Missed seizures, however, occurred more frequently during ECT treatments with concurrent LMT. CONCLUSIONS:: In all patients, seizures of adequate duration could be elicited. The combination was well tolerated. Therapeutic doses of LMT do not seem to have a clinically significant influence on the length of ECT-induced seizures nor on the stimulus dose.

Concurrent Use of Lamotrigine and Electroconvulsive Therapy.

Concurrent use of lamotrigine with ECT in bipolar depression seems safe, did not interfere with routine ECT practice, and allowed for transition to maintenance pharmacotherapy.

Combined Use of Lamotrigine and Electroconvulsive Therapy in Bipolar Depression: A Case Series

OBJECTIVES: To review the literature on the concurrent use of electroconvulsive therapy (ECT) and anticonvulsant drugs (AC) and to provide recommendations to guide clinical practice. METHODS: A MEDLINE search (1985-2006) was performed, using the terms "electroconvulsive therapy," "anticonvulsants," "epilepsy," "carbamazepine," "gabapentin," "lamotrigine," "topiramate," and "valproate," supplemented by manual searches of guidelines and textbooks on ECT. RESULTS: To date, no prospective, randomized and controlled trials examining outcome and safety of the AC-ECT combination have been published. Existing data are from case reports on the use of ECT for psychiatric conditions that are simultaneously treated with AC, and from case reports of patients treated with ECT and AC for epilepsy or for psychiatric conditions with comorbid epilepsy. Apart from an occasional difficulty in eliciting seizures, no severe adverse effects or complications are reported. CONCLUSIONS: The literature that is currently available indicates that ECT can be safely and effectively administered to patients treated with various AC. There is, however, no evidence to combine the 2 treatment modalities to augment therapeutic efficacy.

Anticonvulsants during electroconvulsive therapy: review and recommendations.

Потенциирование, добавление второго антипсихотика или повышение доз атипичных антипсихотиков

The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone,and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms. However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice. This article reviews the current evidence for these increasingly common means of treating
schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation. To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings. One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy. A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine. The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects. With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation. Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses.

Increasing the dose in patients with partial responses or breakthrough symptoms is faster and easier than switching to another agent, and it is possible that it would result in improved efficacy. There are also some patients who may be
rapid metabolizers, and thus require higher doses than the average patient. However, although some patients may benefit from higher doses, this method of treatment can
increase the risk of side effects, especially motor side effects. Positron emission tomography (PET) data demonstrate that dopamine 2 (D2) receptor occupancy of 70% is necessary for therapeutic benefits, while occupancy greater than 80% is associated with extrapyramidal symptoms [34]. Doses at the upper end of the recommended range for the first-line antipsychotics may already result in 80% occupancy of D2
receptors in the nigrostriatal pathway [35], so that doses above those ranges are more likely to induce EPS. In particular, the risk of EPS with risperidone is dose-
dependent and may even increase above 4 mg/day

In summary, there is currently no compelling evidence to support long-term antipsychotic polypharmacy. There are few theoretical benefits and many theoretical detriments. Although individual patients may respond to antipsychotic
polypharmacy without side effects, adequate trials have not yet determined the costs versus the benefits of this option.

The evidence for augmentation of atypical antipsychotics varies depending on the particular agent. Controlled studies with conventional antipsychotics suggest that augmentation with benzodiazepines is most likely useful as an acute treatment for patients with agitation and hostility, but controlled studies do not exist for atypical antipsychotics. As mentioned earlier, a multicenter double-blind study demonstrates the safety and efficacy of only one augmenting agent in schizophrenia, namely divalproex [96]. Controlled studies combining divalproex and an atypical antipsychotic also show additive benefits in bipolar disorder, strengthening the appeal of this particular augmenting strategy [167-168]. Unfortunately, there are no controlled data for augmentation of atypical antipsychotics with other anticonvulsants even though this is a frequent and expensive practice, especially with gabapentin. Thus, the evidence currently suggests that divalproex is perhaps the best evidence-based augmentation option when multiple monotherapies fail

A Critical Review of Atypical Antipsychotic Utilization: Comparing
Monotherapy with Polypharmacy and Augmentation

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)

Комбинирование клозапина с ламотриджином

Schizophrenia patients routinely are treated with polypharmacy--often with antidepressants or anticonvulsants--in attempts to improve negative symptoms, aggression, and impulsivity. Most adjuncts, however--including divalproex, antidepressants, and lithium--have shown very small, inconsistent, or no effects. The only agent with a recent meta-analysis supporting its use as augmentation in treatment-resistant schizophrenia is lamotrigine, an anticonvulsant approved for use in epilepsy...

Clozapine Augmentation with Lamotrigine

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

Клептомания

Additionally, there is some suggestion that selective serotonin reuptake inhibitors, the treatment of choice for obsessive compulsive disorder,may lack efficacy for kleptomania. Instead, other medications (lithium, anti-epileptics, and opioid antagonists) have shown early promise
in treating kleptomania. Evidence suggests that theremay be subtypes of kleptomania that aremore likeOCD, whereas others have more similarities to addictive and mood disorders.
Understanding and Treating Kleptomania:NewModels and New Treatments

терапия деперсонализации

For example, a number of studies suggest that opioid receptor antagonists such as naltrexone and naloxone are useful in at least a subgroup of patients. In spite of initial expectations, the use of lamotrigine as a sole medication has not been found useful. However, open-label trials suggest that its use as an add-on treatment with selective serotonin reuptake inhibitors (SSRIs) is beneficial in a substantial number of patients. Similarly, the use of clonazepam, particularly in conjunction with SSRI antidepressants, appears to be beneficial in patients with high levels of background anxiety.
Depersonalization disorder: pharmacological approaches

Two recent controlled medication trials, one with lamotrigine and one with fluoxetine, failed to show efficacy. There is some evidence for dysregulation of endogenous opioid systems in depersonalization, and a few studies have suggested that opioid antagonists may have efficacy in the treatment of dissociation and depersonalization symptoms. In this prospective open treatment trial, 14 subjects were recruited and treated with naltrexone for 6 weeks to a maximum dose of 100 mg/d (first 7 subjects) or 10 weeks to a maximum dose of 250 mg/d (next 7 subjects). Mean naltrexone dose was 120 mg/d. There was an average 30% reduction of symptoms with treatment, as measured by 3 validated dissociation scales. Three patients were very much improved, and 1 patient was much improved with naltrexone treatment.
An open trial of naltrexone in the treatment of depersonalization disorder