Акампросат, механизм действия

Throughout the years, however, the molecular target of acamprosate has remained elusive. Because of structural similarities, initial hypotheses centered on the possibility that acamprosate may act as a GABA-mimic or otherwise modulate GABA-ergic transmission. There is, however, little in the in vivo profile of acamprosate to suggest similarities with drugs known to enhance GABA-ergic transmission. In fact, a lack of sedative–ataxic or addictive properties is among the clinical advantages of acamprosate. Once it became clear that acamprosate’s mechanism of action is likely to involve modulation of glutamatergic function, several potential mechanisms were explored. For instance, acamprosate was shown to possess some partial agonist activity on the NMDA receptor complex via actions at its polyamine site. This would potentially allow it to act as a functional antagonist during hyperglutamatergic states. However, experiments failed to demonstrate this kind of functional activity. More recently, focus shifted to potential activity of acamprosate at metabotropic glutamate receptors (mGluRs). This was prompted, for example, by observations that acamprosate blocked neurotoxicity induced by trans-ACPD, an mGluR agonist with affinity for mGluR1 and mGluR5 receptors (Kiefer and Mann, 2010).

Over the years, the notion has become widely accepted that, although we may not know its exact mechanism of action, acamprosate is ‘a functional glutamate antagonist’. The paper by Spanagel et al (2005) in this issue fundamentally challenges this notion. The paper presents multiple lines of evidence that the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries. The authors first thoroughly excluded agonist as well as antagonist activity of acamprosate at the glycine or glutamate sites of the NMDA receptor, respectively, as well as at the mGluR5 receptor. They then went on to demonstrate in vivo that, in contrast to the Ca++ salt, the sodium salt of acamprosate did not suppress relapse-like drinking. Conversely, the delivery of comparable amounts of Ca++ using a different carrier, gluconate, replicated suppression of relapse-like drinking. These animal findings are supported by secondary analyses of clinical trial data, which indicate that in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.

Acamprosate: An Alcoholism Treatment That May Not Be What We Thought

Комбинация эсциталопрама с арипипразолом в терапии коморбидной депрессии алкогольной зависимости

 The effective treatment of depression has been reported to reduce the severity of alcohol use, potentially reflecting improvements in common brain reward circuits. We hypothesized that augmentation therapy of escitalopram with aripiprazole would improve depressive symptoms as well as reduce craving for alcohol and cue-induced brain activity in patients with co-morbid alcohol dependence and major depressive disorder, compared with treatment with escitalopram alone. Thirty-five subjects with major depressive disorder and alcohol dependence were recruited and randomly assigned into 17 aripiprazole + escitalopram and 18 escitalopram only groups. At baseline and following six weeks of treatment, symptoms of depression, craving for alcohol and brain activity were evaluated. During the six week treatment period, Beck Depression Inventory and clinical global index-severity (CGI-S) scores decreased in both the aripiprazole + escitalopram and escitalopram only groups. In addition, following the treatment period, the Korean alcohol urge questionnaire scores in the aripiprazole + escitalopram group were reduced from 23.3±8.4 to 14.3±4.9, compared with those of the escitalopram group of from 21.6±8.4 to 19.3±7.1 ( F=13.1, p < 0.01 ). The activity within the anterior cingulate was increased in response to the presentation of alcohol drinking scenes following treatment in the aripiprazole + escitalopram group. The change of brain activity within the left anterior cingulate gyrus in all patients with co-morbid alcohol dependence and major depressive disorder was negatively correlated with the change in craving for alcohol. These findings suggest that the effects of aripiprazole on anterior cingulate cortex might mediate the successful treatment of alcohol dependence in patients with major depressive disorder.

Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: Clinical and neuroimaging evidence

Празозин как средство от ночных кошмаров

Mayo Clinic investigators have completed a systematic literature review of prazosin in the treatment of nightmares. Researchers investigated 12 prazosin studies, four of which were randomized controlled trials.
“The studies showed the drug was well-tolerated and can take effect rapidly, within days to weeks, and some patients reported a return of nightmares when the course of prazosin was stopped,” said Simon Kung, M.D., principal investigator of the study.

 Blood Pressure Drug Relieves PTSD Nightmares

Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence

Алкоголизм функционально хорошо заменяется депрессивным состоянием партнера. В системной модели "Спасатель" описывается динамика гиперфункциональности и гипофункциональности в семье: тот, кто спасает - гиперфункционал. Рядом с гиперфункционалом для прочных отношений должен быть гипофункционал. Гипофункциональность задается не только алкоголизмом, наркоманией, но и депрессией. В функциональных семьях так же может развиваться динамика гипер- и гипофункциональности. Например, жена может давать мужу сообщение, что он не достаточно эффективен просто тем, что она сама очень функциональна. Он только соберется что-то сделать, а она уже все сделала. Она - быстрее, энергичнее, и у него формируется ощущение несостоятельности. Один мой клиент рассказывал мне, что в своем первом браке он очень много делал всего по дому. Его первая жена была медлительная и очень нетребовательная. Во втором браке он ничего не делал по хозяйству. Говорил: "Ничего не хочется делать. Жена сама все лучше и быстрее делает, и вообще она всегда недовольна тем, что я делаю". Понятно, что жена была так же недовольна и тем, что муж ничего не делал, не был включен в семейную жизнь.

Семейные мифы в практике системной семейной психотерапии

Баклофен при абстинентном синдроме

A small study in Minnesota has replicated findings from Italy indicating that off-label use of the gamma-aminobutyric acid–derivative baclofen is effective in treating symptoms of alcohol withdrawal syndrome (AWS). The drug has been approved for treating spasticity.

The prospective, double-blind, randomized, placebo-controlled study involved 79 inpatients at risk for AWS. Of these, 44 developed symptoms of AWS and were randomly assigned to receive baclofen 10 mg or placebo 3 times per day. In all, 31 patients completed the 72 hours of observation and assessment required by the study and were available for evaluation.

When the study was unblinded, the researchers found that 1/18 patients in the baclofen group and 7/13 patients in the placebo group (P = .004) required a high dose of benzodiazepines (20 mg or more of lorazepam) during the 72-hour period to control symptoms of AWS.

Baclofen Can Ease Symptoms of Acute Alcohol Withdrawal

налтрексон

While naltrexone has yet to become the huge treatment breakthrough for alcoholism that addiction researchers hoped for it, naltrexone did, in the end, prove to be the first anti-craving medication widely available for alcoholics. Using an opiate antagonist as an aid to the prevention of alcoholic relapse would have been unthinkable without the underpinnings of a neurophysiological model of addiction. Various investigators have also speculated that naltrexone, the drug used as an adjunct of heroin withdrawal therapy, may find use against symptoms of marijuana withdrawal in people prone to marijuana dependence

Naltrexone has something of a mixed reputation, however, in part due to its use in the highly controversial practice of “rapid detox.” Naltrexone, like methadone and buprenorphine, blocks the heroin high in a relatively neutral manner. It does so by knocking the opiate molecule off its receptors and replacing it with “dead weight,” so to speak. Naltrexone would seem to be the perfect drug for heroin addicts—but it is not. It does little to reduce cravings. Like acamprosate for alcohol, another blocking approach, its record of accomplishment is mixed, and the dropout rate is high. There is not even a mild drug-like effect to provide cross-tolerance and dampen the effects of withdrawal, as with methadone. Recently, naltrexone for heroin addiction has been offered as a form of rapid detoxification.

Naltrexone combined with buprenorphine is marketed as Subutex, and represents another treatment modality for opiate addiction. In addition, a University of Minnesota study of kleptomania—the compulsion to steal—showed that naltrexone drastically reduced stealing among a group of 25 shoplifters.

Unfortunately, naltrexone is a potential problem for people with liver disease or hepatitis. At high doses, naltrexone has been implicated in liver damage. More common adverse effects include dizziness, lethargy, and headache.

Addiction Inbox

Нестандартные методы лечения аддикций

Virtual reality graded exposure
VRGET is a rapidly emerging technological intervention with a wide range of promising clinical applications for psychiatric disorders, including posttraumatic stress disorder, phobias, eating disorders, cognitive rehabilitation following stroke, and substance abuse and dependence. Most virtual reality tools are in the early stages of development and are not commercially available. VRGET protocols have been created with the goal of stimulating drug or alcohol craving in patients followed by response prevention and desensitization.

Nonconventional and Integrative Treatments of Alcohol and Substance Abuse

Акампросат

Acamprosate May Be Helpful to Treat Alcohol Dependence

Биомаркеры злоупотребления алкоголем

‘I’m sober, Doctor, really’: Best biomarkers for underreported alcohol use

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

Сертралин+налтрексон

More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol, had delayed relapse to heavy drinking, reported fewer serious adverse events, and tended to not be depressed by the end of treatment.

A Double-Blind, Placebo-Controlled Trial Combining Sertraline and Naltrexone for Treating Co-Occurring Depression and Alcohol Dependence

Низкий уровень гликогена может объяснить, почему некоторые люди всегда очередь агрессивны и склонны к насилию, когда напиваются. К такому выводу пришли финские исследователи.
Найден виновник агрессии алкоголиков