Baldessarini R J
Department of Psychiatry, Harvard Medical School, Boston, Mass.
J Clin Psychiatry. 1989 Apr;50(4):117-26.
Effective antidepressants, including imipramine and monoamine oxidase (MAO) inhibitors, were discovered serendipitously in the 1950s. Many additional agents have been introduced since then, but most are chemically or pharmacologically similar to those known for nearly four decades. Some recently introduced antidepressants offer either lesser or dissimilar side effects, but none exceeds older treatments in efficacy. Selective serotoninpotentiating agents and short-acting MAO-A inhibitors promise efficacy with greater safety. Progress is made difficult because atypical or treatment-resistant patients are more often available for study than typical patients, and because most studies must rely heavily on potentially misleading "standard drug versus new drug" comparisons. Rational development of novel or better agents is slow, in part, due to limited understanding of the biological basis of major affective disorders and some circularity in relating actions of known drugs to pathophysiologic hypotheses. Action mechanisms of antidepressants are subtle and complex: adaptive changes occur in brain monoaminergic neurotransmission following repeated administration of agents of the tricyclic antidepressant (TCA) type that may lead to net facilitation of alpha 1-adrenergic transmission. Important advances have been made in using plasma TCA levels to guide individualization of dosing, in exploring higher doses of antidepressants when ordinary doses prove ineffective, and in recognizing a broadening spectrum of possible indications for antidepressants in adults and children. These indications include panic disorder, obsessive compulsive disorder, attention deficit disorder, and bulimia. Evidence for the prophylactic effects of antidepressants after the first months following recovery from an index episode of major depression is weak, and the treatment of common recurrent or chronic depression remains unsatisfactory. Gains have been made in increasing clinicians' and the general public's awareness of the common occurrence and appropriate treatment of major depression, even when the depression is associated with other medical or psychiatric disorders.
20世纪50年代偶然发现了有效的抗抑郁药，包括丙咪嗪和单胺氧化酶（MAO）抑制剂。从那时起又引入了许多其他药物，但大多数在化学或药理学上与已使用了近40年的药物相似。一些最近引入的抗抑郁药副作用较小或不同，但在疗效上没有超过旧的治疗方法。选择性5-羟色胺增强剂和短效MAO-A抑制剂有望在更高安全性的情况下发挥疗效。进展困难，因为非典型或难治性患者比典型患者更常被用于研究，而且因为大多数研究必须严重依赖可能产生误导的“标准药物与新药”比较。新型或更好药物的合理开发进展缓慢，部分原因是对主要情感障碍的生物学基础了解有限，以及在将已知药物的作用与病理生理假设联系起来时存在一些循环论证。抗抑郁药的作用机制微妙而复杂：反复给予三环类抗抑郁药（TCA）后，脑单胺能神经传递会发生适应性变化，这可能导致α1-肾上腺素能传递的净促进。在利用血浆TCA水平指导个体化给药、在普通剂量无效时探索更高剂量的抗抑郁药以及认识到抗抑郁药在成人和儿童中可能适用的更广泛适应症方面已经取得了重要进展。这些适应症包括惊恐障碍、强迫症、注意力缺陷障碍和贪食症。在首次重度抑郁发作恢复后的头几个月后，抗抑郁药预防作用的证据不足，而且对常见复发性或慢性抑郁症的治疗仍然不尽人意。在提高临床医生和公众对重度抑郁症的常见性和适当治疗的认识方面已经取得了进展，即使抑郁症与其他医学或精神障碍相关。
