简介自从上一版黑皮书以来,一些创新的代理商已经被批准或准备在来年被批准。这些包括新型抗抑郁药,第一种用于治疗精神分裂症的毒蕈碱激动剂,第一种可能被批准用于治疗PTSD(创伤后应激障碍)的迷幻药,和第一种用于治疗阿尔茨海默病的疾病改善药物。在过去的18个月中,有三种新的抗抑郁药进入市场。第一个,Auvelity,安非他酮和右美沙芬的组合,利用两种药物之间的药代动力学和药效学协同作用85.右美沙芬具有多种药效学特性,包括对NMDA受体和Sigma1受体的作用,添加安非他酮的间接去甲肾上腺素激动剂特性。右美沙芬如何通过CYP2D6同工酶快速代谢为可能具有μ阿片激动剂特性的右旋糖素。与安非他酮的组合,CYP2D6抑制剂,抑制右美沙芬的代谢,允许更一致的治疗水平。每天两次的右美沙芬45mg和每天两次的安非他酮SR105mg的组合在加速抗抑郁反应和实现缓解方面似乎比等效剂量的单独安非他酮更有效。然而,目前尚不清楚该组合如何与每天300-450毫克的安非他酮的更典型剂量进行比较。Auvelity的第三阶段计划,表明该药物耐受性良好,最常见的副作用是头晕,头痛,和口干。862023年批准的另一种新型抗抑郁药是zuranolone(Zurzuvae)。Zuranolone是静脉利沙诺酮的口服类似物,就像布雷沙诺酮一样,被批准用于产后抑郁症的治疗。83Zuranolone优于brexanalone的优势很多。虽然brexanolone是一种60小时的静脉输液,必须在医疗机构进行,zuranolone是一种每天一次的口服药物,通常在家服用。像brexanolone一样,与大多数抗抑郁药不同,zuranolone有一个短疗程,只持续了14天。Zuranolone\'s,就像布雷沙诺酮一样,被认为主要充当GABA-a受体的变构调节剂。尽管只有14天的治疗,Zuranolone在产后抑郁症患者中产生了临床上有意义的改善,在第15天,并持续到第45天或治疗结束后的1个月。Zuranolone是一种附表IV药物。临床试验中最常见的副作用是嗜睡,36%的参与者报告这种副作用,而安慰剂中只有6%。84其他常见的副作用包括头晕,腹泻和疲劳。虽然FDA拒绝批准Zuranolone作为单一疗法或作为标准抗抑郁药的辅助治疗,在非产后重性抑郁症中,有积极的研究,尽管效应大小较小,活动持续时间不那么一致。Zuranolone可能会继续在其他抑郁综合征中进行研究,例如伴有焦虑困扰的抑郁症。2023年底批准的第三种“新”抗抑郁药是吉吡龙(Exxua)。Gepirone并不完全是一种新的或新颖的抗抑郁药,最初在20年前在美国获得批准。88在最初的NDA申请期间,已经有两项关于Gepirone的积极研究,但也有一些失败,负,或者非信息研究。因此,FDA拒绝最初批准该药物。然而,失败和阴性的试验在抗抑郁药中很常见,经过许多内部辩论,FDA最终同意批准该药物是基于阳性试验和相对有利的副作用.Gepirone,像Buspirone,是5HT1a受体的部分激动剂和5HT2拮抗剂。因此,吉吡龙不会与性副作用有关,体重增加,或镇静剂。最常见的副作用是头晕,恶心,和失眠,随着时间的推移,许多患者往往会改善。第二代抗精神病药(SGA)仍然是唯一被批准用于耐药性重度抑郁症辅助治疗的药物(除esketamine(Spravato)外)。除了奥氮平(与氟西汀合用;Symbyax),阿立哌唑(消除),喹硫平(Seroquel),布立哌唑(瑞幸),卡利拉嗪(Vraylar)在2022.90年成为最新批准的SGA,在治疗6周后,单用抗抑郁药未能达到足够疗效的MDD患者中,卡利拉嗪每日1.5mg的辅助剂量明显优于安慰剂.有趣的是,3mg剂量的卡利拉嗪效果较差.91卡利拉嗪优于其他一些批准的辅助SGA的主要优点是易于给药,起始的1.5毫克剂量是大多数人的最佳治疗剂量,和较低的代谢副作用负担,大多数受试者在短期试验中体重增加有限或没有体重增加。最常见的副作用是静坐不能/躁动,疲劳,和恶心。Lumateperone(Caplyta)在重度抑郁症的辅助治疗中也具有积极的III期数据,并且是2024年末批准的理想文件。精神药理学的另一个最近的主要发展是迷幻药在精神疾病治疗中的重新出现。首先是MDMA(苯乙胺3,4-亚甲二氧基甲基苯丙胺)辅助的心理疗法,用于治疗PTSD。2023.87年末,FDA接受了MDMA治疗PTSD的新药申请(NDA),因为该药物被FDA快速追踪为“突破性”治疗,预计将在2024年夏天获得批准。MDMA辅助心理治疗治疗PTSD的II期和III期数据非常一致且令人印象深刻。然而,独立评论指出了这些研究中的重大缺陷,包括由于功能性脱盲而引入的偏倚;迷幻研究中的几乎所有患者都可以猜测他们是否服用了活性药物或安慰剂.功能性脱盲,辅助心理治疗缺乏标准化以及MDMA的滥用潜力,可能会推迟FDA的批准。这些试验中的典型方案包括3次心理治疗准备疗程,然后每月一次给药(持续约8小时),并分剂量使用120-160mg的剂量。通常每月有3次给药,每次接受3次综合心理治疗,以帮助受试者处理和了解他们在给药过程中的经历.在最近的第三阶段试验中,超过70%的受试者不再符合PTDS标准,而仅接受心理治疗和安慰剂治疗的受试者只有46%.89唯一批准的治疗PTSD的药物是两种SSRIs,帕罗西汀和舍曲林.这些药物仅影响PTSD的某些方面,只有20-30%的药物达到缓解水平的反应。因此,MDMA辅助的心理治疗似乎比SSRIs的缓解和反应水平高得多。由于MDMA不是连续服用的,MDMA的副作用往往是短暂的。副作用包括肌肉紧绷,恶心,食欲减退,出汗过多,感到寒冷和头晕。由于摇头丸目前是附表I药物,很可能会实施严格的风险评估缓解(REM)计划,并指定数量有限的中心和临床医生对PTSD进行MDMA辅助心理治疗.除了MDMA,psilocybin辅助的心理治疗正在进行治疗顽固性抑郁症的3期试验,但最早在2025年底之前不太可能可用。可以说,自1990年氯氮平在美国推出以来,还没有真正新颖的抗精神病药。所有第一代抗精神病药都是多巴胺2拮抗剂,第二代药物涉及5HT2拮抗作用与D2阻断作用的一定比例。2023年,FDA接受了Xenomaline/trophasium(KarXT)的应用,该药物可能成为第一种被批准用于治疗精神分裂症的毒蕈碱M1M4激动剂。82,83将Tropsium作为毒蕈碱拮抗剂添加,以阻断毒蕈碱激动剂的外周胆碱能作用。Xenomaline/trophium似乎可有效治疗精神分裂症的阳性和阴性症状。在一项407名精神分裂症患者的3期研究中,Xenomaline/trocium的剂量为Xenomaline/50mg/trocium,每天两次至125mg/30mg,每天两次,在治疗5周内,与安慰剂相比,在治疗两者和阴性症状方面显着更有效。正如预期的那样,Xenomaline/trocium的副作用与目前所有可用的抗精神病药非常不同。没有EPS的风险,因为它不是多巴胺拮抗剂,Xenomaline/troscium与显着的代谢作用无关。副作用本质上是胆碱能的,包括便秘,口干,和恶心。预计将于2024年9月做出决定。2023年还批准了第一种用于治疗阿尔茨海默病的疾病修饰药物,莱卡尼玛(Lequembi)。虽然乙酰胆碱酯酶抑制剂和美金刚已经有几十年了,这些药物可以适度改善阿尔茨海默病患者的认知,并且不会改变疾病的进展过程。Lecanemab是一种IV单克隆抗体,其靶向去除大脑中的β-淀粉样蛋白以及已知对神经元组织有毒的原纤维。当在疾病早期给予时,Lecanemab治疗的患者在认知和功能的某些指标方面的下降比安慰剂治疗18个月(约1年半)的患者少27%.不知道治疗超过18个月是否会随着时间的推移显示出更小或更大的下降。然而,有模拟研究表明,Lecanemab可能会适度减少进展为严重阿尔茨海默病并需要机构护理的患者数量。标准剂量为10mg/kg,每2周1小时通过静脉给药,持续18个月。Lecanemab通常在输液中心给药,以便可以监测副作用。Lecanemab最严重的副作用是与脑水肿和微出血相关的淀粉样蛋白相关的成像异常(ARIA)。ARIA可发生在高达15%的患者中。更常见的副作用是头痛和恶心。虽然这些新药在临床实践中的作用还有待观察,它们确实代表了一种治疗神经精神疾病的方法,这种方法与过去半个世纪的药物疗法明显不同。似乎一些无法对传统药物治疗产生反应或耐受的患者可能会在这些新药物中找到希望。
Introduction Since the last edition of the Black Book, several innovative agents have been approved or are poised to be approved in the coming year. These include novel antidepressants, the first muscarine agonist for the treatment of schizophrenia, the first psychedelic which may be approved for the treatment of PTSD (Post Traumatic Stress Disorder), and the first disease modifying drug for the treatment of Alzheimer\'s disease. Three new antidepressants have come to the market in the past 18 months. The first of those, Auvelity, the combination of bupropion and
dextromethorphan, takes advantage of a pharmacokinetic and pharmacodynamic synergism between the two drugs.85
Dextromethorphan has several pharmacodynamic properties including actions on the NMDA receptor and the Sigma 1 receptor, adding to the indirect norepinephrine agonist properties of bupropion. How
Dextromethorphan is rapidly metabolized via the CYP2D6 isoenzyme to dextrophan that may have mu opioid agonist properties. The combination with bupropion, a CYP2D6 inhibitor, inhibits the metabolism of
dextromethorphan allowing for more consistent therapeutic levels. The combination of
dextromethorphan 45 mg twice per day and bupropion SR 105 mg twice daily appears to be more effective than an equivalent dose of bupropion alone both in speeding up antidepressant response and achieving remission. However, it\'s not clear at this time how the combination would compare with a more typical dose of bupropion of 300-450 milligrams a day range. The phase III program for Auvelity, showed that the drug was well tolerated with the most common side effects being dizziness, headache, and dry mouth.86 Another novel antidepressant agent approved in 2023 is zuranolone (Zurzuvae). Zuranolone is an oral analog of IV brexanalone, and like brexanolone, was approved for the treatment of post-partum depression.83 The advantages of zuranolone over brexanalone are many. While brexanolone is a 60-hour intravenous infusion that must be administered in a health care facility, zuranolone is a once/day oral medication that is usually taken at home. Like brexanolone, and unlike most antidepressants, zuranolone has a short course of treatment, lasting just 14 days. Zuranolone\'s, as does brexanolone, is thought to act primarily as allosteric modulator of the GABA-a receptors. Despite only 14 days of treatment, zuranolone produced in depression in post-partum patients a clinically and significantly meaningful improvement at day 15 and continued to day 45 or 1 month past the end of treatment. Zuranolone is a schedule IV drug. The most common side effect in clinical trials was somnolence with 36% of participants reporting this side effect vs only 6% of those on placebo.84 Other common side effects included dizziness, diarrhea and fatigue. While the FDA declined to approve zuranolone as monotherapy or as an adjunctive treatment to standard antidepressants in major depression itself, there are positive studies in non-post-partum major depression albeit with smaller effect sizes and less consistent duration of activity. It is likely that zuranolone will continue to be studied in other depressive syndromes such as depression with anxious distress. The third \"new\" antidepressant approved late 2023 was gepirone (Exxua). Gepirone is not exactly a new or novel antidepressant and originally sought approval in the US about 20 years ago.88 There had been two positive studies of gepirone during the original NDA application but also a number of failed, negative, or non-informative studies as well. Thus, the FDA declined to originally approve the drug. However, failed and negative trials are common with antidepressants and after much internal debate, the FDA ultimately agreed to approve the drug based on the positive trials and a relatively favorable side effect profile. Gepirone, like buspirone, is a partial agonist of the 5HT1a receptor and a 5HT2 antagonist. As such, gepirone does not tend to be associated with sexual side effects, weight gain, or sedation. The most common side effects are dizziness, nausea, and insomnia which tend to improve in many patients over time. Second generation antipsychotics (SGAs) continue to be the only class of agents [other than esketamine (Spravato)] approved in adjunctive treatment of resistant major depression. In addition to olanzapine (combined with fluoxetine; Symbyax), aripiprazole (Abilify), quetiapine (Seroquel), brexpiprazole (Rexulti), cariprazine (Vraylar) became the latest SGA to be approved in 2022.90 Adjunctive cariprazine at 1.5 mg daily was significantly more effective than adjunctive placebo in patients with MDD who had failed to achieve an adequate response with an antidepressant alone after 6 weeks of treatment. Interestingly, a 3 mg dose of cariprazine was less consistently effective.91 The major advantage of cariprazine over some of the other approved adjunctive SGA\'s is easy dosing, with the starting 1.5 mg dose being the optimal therapeutic dose for most people, and a lower metabolic side effect burden with most subjects having limited or no weight gain in short term trials. The most common side effect were akathisia/restlessness, fatigue, and nausea. Lumateperone (Caplyta) is also has positive phase III data in the adjunctive treatment of major depression and is expective file for approval in late 2024. Another recent major development in psychopharmacology is the reemergence of psychedelics in the treatment of psychiatric disorders. The first of these is MDMA (phenethylamine 3,4-methylenedioxymethamphetamine) assisted psychotherapy for the treatment of PTSD. A New Drug Application (NDA) was accepted by the FDA for MDMA in the treatment of PTSD in late 2023.87 Because the drug is being fast tracked as a \"breakthrough\" treatment by the FDA, it was expected to see approval in the summer of 2024. The phase II and III data for MDMA assisted psychotherapy in the treatment of PTSD have been quite consistent and impressive. However, independent reviews have pointed to significant deficiencies in these studies including the bias introduced because of functional unblinding; virtually all patients in psychedelic studies can guess whether they got the active drug or placebo. The functional unblinding, the lack of standardization of adjunctive psychotherapy as well as the abuse potential of MDMA, may delay an FDA approval. The typical regimen in these trials included 3 preparatory psychotherapy sessions followed by once/month dosing sessions (lasting about 8 hours) and using doses of 120-160 mg in a split dose. There were typically 3 monthly dosing sessions, each followed by 3 integrative psychotherapy sessions to help subjects process and understand their experiences during the dosing sessions. In the most recent phase 3 trials, over 70% of subjects no longer met criteria for PTDS compared to 46% of those treated with psychotherapy and placebo alone.89 The only approved medications for treating PTSD are two SSRIs, paroxetine and sertraline. These drugs effect only some dimensions of PTSD with only 20-30% achieving a remission level response with these drugs. Thus, MDMA assisted psychotherapy appears to achieve much higher levels of remission and response than has been true for the SSRIs. Since MDMA is not taken continuously, side effects from MDMA tend to be short lived. Side effects have included muscle tightness, nausea, diminished appetite, excessive sweating, feeling cold and dizziness among others. Since MDMA is currently a schedule I drug, it is likely that a rigorous Risk Evaluation Mitigation (REMs) program will be put in place and a limited number of centers and clinicians will be designated to perform MDMA assisted psychotherapy for PTSD. In addition to MDMA, psilocybin-assisted psychotherapy is in phase 3 trials for treating resistant depression but unlikely to be available before late 2025 at the earliest. An argument can be made that there has not been a truly novel antipsychotic since the introduction of clozapine in the US in 1990. All first-generation antipsychotics have been dopamine 2 antagonists and second-generation drugs have involved some ratio of 5HT2 antagonism to D2 blockade. In 2023, the FDA accepted the application of xenomaline/tropsium (KarXT) which may become the first muscarinic M1M4 agonist approved for the treatment of schizophrenia.82,83 Tropsium is added as a muscarine antagonist to block the peripheral cholinergic effects of a muscarine agonist. Xenomaline/tropsium appears to be effective in treating both positive and negative symptoms of schizophrenia. In a phase 3 study of 407 patients with schizophrenia, xenomaline/tropsium at doses of xenomaline/50 mg/tropsium 20 mg twice daily up to 125 mg/30 mg twice daily was significantly more effective than placebo in treating both and negative symptoms over 5 weeks of treatment. As would be expected, the side effect profile of xenomaline/tropsium is very different that all currently available antipsychotics. There is no risk of EPS as it is not a dopamine antagonist, and xenomaline/tropsium is not associated with significant metabolic effects. The side effects are cholinergic in nature and include constipation, dry mouth, and nausea. A decision is expected in September of 2024. The year 2023 also saw the approval of the first disease modifying drug in the treatment of Alzheimer\'s disease, lecanemab (Lequembi). While acetylcholinesterase inhibitors and memantine have been available for decades, these drugs modestly improve cognition in Alzheimer\'s disease patients and do not alter the progressive course of the illness. Lecanemab is an IV monoclonal antibody that targets the removal of beta-amyloid in the brain as well proto-fibrils that are also known to be toxic to neuronal tissue. When given early in the course of the illness, patients treated with Lecanemab showed 27% less decline on some measures of cognition and function than did patients treated with a placebo over 18 months (about 1 and a half years). It is not known whether treatment for longer than 18 months would show lesser or greater decline over time. However, there are simulation studies that suggest that Lecanemab may modestly reduce the number of patients who progress to severe Alzheimer\'s disease and require institutional care. The standard dose is 10 mg/kg given via IV over one hour every 2 weeks for 18 months. Lecanemab is typically administered in an infusion center so that side effects can be monitored. The most serious side effects of Lecanemab are amyloid related imaging abnormalities (ARIA) that are associated with brain edema and microhemorrhages. ARIA can occur in up to 15% of patients. More common side effects are headache and nausea. While it remains to be seen how useful these new agents will be in clinical practice, they do represent an approach to treating neuropsychiatric disorders that are a notable departure from the pharmacotherapy of the past half century. It seems likely that some patients who have not been able to respond to or tolerate traditional pharmacotherapy will find hope in these new medications.