Антиконвульсанты при тревожных расстройствах

Can Anticonvulsants Help Patients With Anxiety Disorders?

Терапия генерализованного тревожного расстройства

Studies comparing antidepressants with benzodiazepines in the treatment of GAD showed that although benzodiazepines work quickly, the antidepressants lower anxiety more effectively in the long term.[11] Antidepressants that have been approved by the United States Food and Drug Administration (FDA) for the treatment of GAD are extended-release venlafaxine,[12] duloxetine,[13] escitalopram,[14] and paroxetine.[15] Although not FDA approved, citalopram has also been found to be effective for the treatment of GAD.[16] Whereas benzodiazepines have been shown effective for shortterm anxiety, they may worsen depression, a common comorbidity of GAD, and cause other cognitive adverse effects such as sedation and anterograde amnesia. Individuals with a history of substance abuse or dependence should not use benzodiazepines, but patients with no such history rarely abuse these agents and can use them safely.[17] Buspirone and pregabalin also have proven efficacy for GAD.[18–21]

Table 1. Summary of Clinical Trials of Adjunctive Use of Atypical Antipsychotics for Treatment-Resistant Generalized Anxiety Disorder^a

Agent	Study Design	No. of Patients	Study Duration (wks)	Mean Daily Dose (mg)	Change in Assessment Score	Mean Weight Gain (lbs)b
Aripiprazole[30]	Open label	17	4.9	16.9	CGI-S: −1.6	NR
Aripiprazole[31]	Open label	10	9	NR	HAM-A: −20.6	7.1
Aripiprazole[32]	Open label	9	6	13.9	HAM-A: −12 CGI-I: 8 of 9 patients rated as much improved or very much improved	NR
Aripiprazole[33]	Open label	23	8	10.5	HAM-A: −6.7 CGI-S: −1	2.5
Olanzapine[34]	Randomized, controlled	21	6	8.7	HAM-A: olanzapine −7 vs placebo −3.9 (p=0.4) CGI-S: 67% of patients rated as not at all ill or borderline ill	11
Quetiapine[35]	Randomized, controlled	58	8	182	HAM-A: quetiapine −12.5 vs placebo −5.9 (p=0.002)	5.2
Quetiapine[36]	Randomized, controlled	22	8	120	HAM-A: quetiapine −2.6 vs placebo −0.3 (p=0.98)	2.7
Quetiapine[37]	Open label	40	12	386	HAM-A: −20.6	1.1
Risperidone[38]	Open label	16	8	1.12	HAM-A: −6.75 CGI-S: −1.53	3.9
Risperidone[39]	Randomized, controlled	40	5	1.1	HAM-A: risperidone −9.8 vs placebo −6.2 (p=0.034)	2.3
Risperidone[40]	Randomized, controlled	390	4	0.86	HAM-A: risperidone −9.26 vs placebo −9.12 (p=0.858) PaRTS-A: risperidone −8.54 vs placebo −7.61 (p=0.265)	2.65
Ziprasidone[41]	Open label	13	7	40	HAM-A: −11.2	0.2

HAM-A = Hamilton Rating Scale for Anxiety (lower scores indicate less severe symptoms of anxiety); CGI-S = Clinical Global Impressions-Severity (lower scores indicate less severe illness); CGI-I = Clinical Global Impression–Improvement; NR = not reported; PaRTS-A = Patient-Rated TroublingSymptoms for Anxiety.
^aAll atypical antipsychotic treatment was added to current antidepressant therapy.
^bIn patients who received the atypical antipsychotic.

Adjunctive Use of Atypical Antipsychotics for Treatment-resistant Generalized Anxiety Disorder

Прегабалин: злоупотребление, зависимость, синдром отмены

Pregabalin is a GABA-analog that selectively binds to the alpha2 delta subunit of voltage-gated calcium channels. It inhibits the release of excitatory neurotransmitters and increases neuronal GABA levels. Like some other compounds that modulate GABA-ergic neurotransmission, pregabalin might have a potential for abuse. Our patient had a history of drug addiction, which may be important in the reward effect of pregabalin. We therefore recommend being especially cautious when using pregabalin to treat patients with a history of drug or alcohol dependence.

Pregabalin Abuse, Dependence, and Withdrawal: A Case Report

Pittenger C, Desan PH: Gabapentin abuse, and delirium tremens upon gabapentin withdrawal. J Clin Psychiatry 2007

Vicctorio-Vigneau C, Guerlais M, Jolliet P: Abuse, dependency and withdrawal with gabapentin: a first case report

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

Влияние современных антиконвульсантов на когнитивные функции

"BACKGROUND: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction, a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. We measured the cognitive effects of 12 weeks of pregabalin in healthy volunteers. METHODS: Thirty-two healthy volunteers were randomized in a double-blind parallel study to receive pregabalin or placebo (1:1). Pregabalin was titrated over 8 weeks to 600 mg/d. At baseline, and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test-retest regressions previously developed from 90 healthy volunteers. Z scores from the placebo and pregabalin groups were compared using Wilcoxon tests. RESULTS: Thirty subjects completed the study (94%). Three of 6 target cognitive measures (Digit Symbol, Stroop, Controlled Oral Word Association) revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin (p < 0.05). These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity (p < 0.01). CONCLUSION: At conventional doses and titration, pregabalin induced mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. Class of Evidence: This study provides Class I evidence that pregabalin 300 mg BID negatively impacts cognition on some tasks in healthy volunteers."

Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo-controlled trial.

"OBJECTIVE: To evaluate the cognitive effects of topiramate (TPM) and gabapentin (GBP). METHODS: Forty healthy volunteers were randomized to a 12-week course of TPM, GBP, or placebo. Doses were gradually escalated over 10 weeks to a maximum of 400 mg/day of TPM or 3,600 mg/day of GBP or to the highest tolerated dose. Subjects were interviewed and examined biweekly. Cognitive testing was performed prior to initiating the drug and again 12 weeks later, at least 2 weeks after achieving plateau dosing. For each subject and cognitive measure, test-retest Z scores were calculated based on regression equations derived from 73 healthy volunteers. Group comparisons utilized the Wilcoxon test. RESULTS: There were significant TPM vs GBP and TPM vs placebo differences in test-retest Z scores for four of six target cognitive measures (Digit Symbol, Story Recall, Selective Reminding, Controlled Oral Word Association), always indicating worse retest performance for subjects receiving TPM. Overall, 12 of 24 cognitive measures were similarly affected. TPM effects were large, and several target measures averaged >2 SD of negative change. One measure was significantly affected by GBP. CONCLUSIONS: Topiramate (TPM) impaired cognitive test performance, whereas gabapentin had minimal effects. The effects of TPM were of sufficient magnitude potentially to affect daily and occupational function."

Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers.