Фармакогенетика антидепрессантов: от генетических находок к предсказательным стратегиям

Постоянно растущий вклад депрессивных расстройств в глобальную картину заболеваний настоятельно требует повышения эффективности используемых для лечения препаратов и оптимизации терапевтических методов. Антидепрессанты являются наиболее часто назначаемыми препаратами для лечения депрессивных расстройств. Однако выработка стандартизованного фармакотерапевтического подхода осложняется генетической гетерогенностью и отсутствием надёжных биомаркеров для предсказания ответов на терапию, биологической вариабильностью метаболизма лекарств, а также множественными побочными эффектами препаратов. По современным оценкам, до 20 % экспрессируемых в нашем головном мозге генов так или иначе вовлечены в патогенез депрессии. Широкомасштабные генетические и геномные исследования выявили ряд потенциально прогностических генов. Также было показано, что эффективность и переносимость антидепрессантов напрямую зависят от вариабельности в активности ферментов, метаболизирующих медикаменты. Почти все современные антидепрессанты метаболизируются ферментами семейства цитохрома Р450 (семейство CYP). Наиболее многообещающим направлением исследований считается метод Полногеномного Поиска Ассоциаций (GWAS). Он направлен на детальное изучение ассоциаций между геномными вариациями и фенотипическими признаками. В исследованиях такого типа обычно сравнивают геномы депрессивных больных, имеющих разные фенотипы, с геномами контрольной группы, состоящей из аналогичных по возрасту, полу и другим признакам здоровых людей. Следует отметить, что, несмотря на анализ крупных когорт пациентов, в проведённых GWA-исследованиях пока не удаётся надёжно воспроизвести результаты других аналогичных исследований. Грандиозная гетерогенность определяющих развитие депрессии генов и их плейотропный эффект в сочетании с мощным влиянием факторов внешней среды объясняют сложность получения значимых и воспроизводимых результатов. Однако, несмотря на это, активная научная работа в разных направлениях позволяет клиницистам и их пациентам надеяться уже в ближайшие годы получить целый ряд схем скорейшего и гарантированного выхода в ремиссию.

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