Gin S. Malhi, Uyen Le, Cornelia Kaufmann, Erica Bell
<p>In an investigator-initiated study<sup>1</sup> designed to determine the positioning of esketamine in the treatment (PoET) of depression, we have treated patients with severe depression. As it is a naturalistic study, we have no stipulations as to the antidepressant treatment the person is taking when commencing add-on esketamine therapy, which is administered via bi-weekly insufflation under medical supervision. Most patients that are referred are taking SSRIs, SNRIs or TCAs, and occasionally are taking MAOIs or novel agents such as vortioxetine. However, in one patient who had trialled most treatments, the physician had resorted to trialling lamotrigine even though the patient had no history of bipolar disorder, possibly because of the complexity of the illness (number of comorbidities) and lack of response.</p><p>It is this case, of a 44-year-old Caucasian female (LE) with a current psychiatric history of treatment resistant depression (TRD), along with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD) and iatrogenic benzodiazepine dependence that we present here. Previous diagnoses also included orthorexia in recovery and substance misuse in young adulthood. Her medical history includes osteoporosis and ulcerative colitis, but she has been off steroids since 2015, and does not smoke, consume alcohol or use substances.</p><p>In late 2018, LE, then 40 years old, was diagnosed with major depressive disorder with anxiety. There was no significant precipitant for her depressive episodes and because of her illness, she stopped working in 2019. Her depressive symptoms included sadness, numbness, anhedonia, low self-worth, feelings of helplessness and hopelessness, loss of appetite, detachment and passive suicidal ideation. She described her depression as “<i>depression with unbearable pain</i>”, and she was “<i>unable to see the future</i>”. In addition to receiving psychological and dietetic treatments weekly, she also trialled multiple pharmacological treatments including SSRIs, SNRIs, TCAs, MAOIs, atypical antipsychotics and lithium augmentation (see Figure 1). She experienced a partial response with some medications but also had severe side effects. She also underwent a course of rTMS, which she reported “<i>did nothing for me, I felt like it did less than an SSRI</i>”.</p><p>In January 2024, the patient was referred to the CADE clinic<sup>2</sup> and screened for PoET. After an extensive assessment process, we deemed the patient suitable for enrolment. She consented and commenced the study in January 2024. As per our protocol, she received esketamine treatments twice weekly for 4 weeks. At the time of enrolment, LE was taking lamotrigine 200 mg daily, diazepam 4.5 mg daily (slowly weaning off, but kept at a stable dose for the duration of the trial) and suvorexant for sleep. She completed a baseline questionnaire and received her first esketamine treatment in January 2024. She completed the course by mid-February having
{"title":"Adding esketamine to lamotrigine to treat major depression: Combinatorial synergism, augmentation, or neither?","authors":"Gin S. Malhi, Uyen Le, Cornelia Kaufmann, Erica Bell","doi":"10.1111/bdi.13448","DOIUrl":"10.1111/bdi.13448","url":null,"abstract":"<p>In an investigator-initiated study<sup>1</sup> designed to determine the positioning of esketamine in the treatment (PoET) of depression, we have treated patients with severe depression. As it is a naturalistic study, we have no stipulations as to the antidepressant treatment the person is taking when commencing add-on esketamine therapy, which is administered via bi-weekly insufflation under medical supervision. Most patients that are referred are taking SSRIs, SNRIs or TCAs, and occasionally are taking MAOIs or novel agents such as vortioxetine. However, in one patient who had trialled most treatments, the physician had resorted to trialling lamotrigine even though the patient had no history of bipolar disorder, possibly because of the complexity of the illness (number of comorbidities) and lack of response.</p><p>It is this case, of a 44-year-old Caucasian female (LE) with a current psychiatric history of treatment resistant depression (TRD), along with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD) and iatrogenic benzodiazepine dependence that we present here. Previous diagnoses also included orthorexia in recovery and substance misuse in young adulthood. Her medical history includes osteoporosis and ulcerative colitis, but she has been off steroids since 2015, and does not smoke, consume alcohol or use substances.</p><p>In late 2018, LE, then 40 years old, was diagnosed with major depressive disorder with anxiety. There was no significant precipitant for her depressive episodes and because of her illness, she stopped working in 2019. Her depressive symptoms included sadness, numbness, anhedonia, low self-worth, feelings of helplessness and hopelessness, loss of appetite, detachment and passive suicidal ideation. She described her depression as “<i>depression with unbearable pain</i>”, and she was “<i>unable to see the future</i>”. In addition to receiving psychological and dietetic treatments weekly, she also trialled multiple pharmacological treatments including SSRIs, SNRIs, TCAs, MAOIs, atypical antipsychotics and lithium augmentation (see Figure 1). She experienced a partial response with some medications but also had severe side effects. She also underwent a course of rTMS, which she reported “<i>did nothing for me, I felt like it did less than an SSRI</i>”.</p><p>In January 2024, the patient was referred to the CADE clinic<sup>2</sup> and screened for PoET. After an extensive assessment process, we deemed the patient suitable for enrolment. She consented and commenced the study in January 2024. As per our protocol, she received esketamine treatments twice weekly for 4 weeks. At the time of enrolment, LE was taking lamotrigine 200 mg daily, diazepam 4.5 mg daily (slowly weaning off, but kept at a stable dose for the duration of the trial) and suvorexant for sleep. She completed a baseline questionnaire and received her first esketamine treatment in January 2024. She completed the course by mid-February having","PeriodicalId":8959,"journal":{"name":"Bipolar Disorders","volume":"26 5","pages":"500-504"},"PeriodicalIF":5.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bdi.13448","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>People with bipolar disorders (BD) often display cognitive dysfunction, especially in verbal and working memory, processing speed and executive functions, which lead to poor occupational outcomes even more than residual symptoms.<span><sup>1</sup></span> Consequently, there is a constant effort to find treatments that might improve cognition and eventually global functioning in BD.</p><p>Several observations point to hypodopaminergic state as a driver of cognitive impairment in BD; therefore, increasing dopamine levels has been attempted as a strategy to ameliorate cognition.</p><p>Both stimulant and non-stimulant ADHD medications increase dopamine and norepinephrine brain levels, making them good candidates for treating cognitive dysfunction in BD. However, there has been a concern as to whether these medications are well tolerated, and specifically whether their use may induce (hypo)manic symptoms or episodes in persons with BD.</p><p>Stemming from these premises, the Targeting Cognition task force of the International Society for Bipolar Disorders (ISBD) conducted a systematic review on the efficacy and tolerability of ADHD medications in treating cognitive dysfunction in BD.<span><sup>2</sup></span></p><p>The review reassures on tolerability, concluding that when BD is properly stabilized, the risk of treatment-emergent manic episodes due to the use of stimulant or non-stimulant ADHD medications is not higher than with placebo or other control conditions. Thus, methylphenidate, lisdexamfetamine, armodafinil, modafinil or bupropion can be safely employed unless BD is pharmacologically stabilized. Beyond the reviewed evidence coming from Randomized Controlled Trials, a large Swedish registry study on 2307 adults with BD who later initiated methylphenidate for concurrent ADHD found no evidence for an association between methylphenidate and treatment-emergent mania among those on concomitant mood stabilizers. On the other hand, those treated with the stimulant alone had a 6.7 times increased rate of manic episodes within 3 months of medication initiation.<span><sup>3</sup></span> Hence, we might say that there is sufficient evidence not to discourage the use of ADHD medications in adequately stabilized BD.</p><p>However, the most compelling research aim was to review the efficacy of ADHD medications as cognitive enhancers in BD: the authors, based on evidence coming from three studies, concluded that there is insufficient data to assert that ADHD medications can improve cognition in BD. The first reviewed study was designed to assess the efficacy of adjunctive methylphenidate in reducing manic symptoms in acutely manic subjects. For safety reasons, the study lasted 2.5 days, after which methylphenidate was deemed ineffective and therefore stopped. The very short period of observation likely speaks for the observed lack of cognitive effect of methylphenidate. The second study, which evaluated the pro-cognitive effects of clonidine on manic subj
{"title":"ADHD medications for cognitive impairment in bipolar disorders","authors":"Virginio Salvi","doi":"10.1111/bdi.13459","DOIUrl":"10.1111/bdi.13459","url":null,"abstract":"<p>People with bipolar disorders (BD) often display cognitive dysfunction, especially in verbal and working memory, processing speed and executive functions, which lead to poor occupational outcomes even more than residual symptoms.<span><sup>1</sup></span> Consequently, there is a constant effort to find treatments that might improve cognition and eventually global functioning in BD.</p><p>Several observations point to hypodopaminergic state as a driver of cognitive impairment in BD; therefore, increasing dopamine levels has been attempted as a strategy to ameliorate cognition.</p><p>Both stimulant and non-stimulant ADHD medications increase dopamine and norepinephrine brain levels, making them good candidates for treating cognitive dysfunction in BD. However, there has been a concern as to whether these medications are well tolerated, and specifically whether their use may induce (hypo)manic symptoms or episodes in persons with BD.</p><p>Stemming from these premises, the Targeting Cognition task force of the International Society for Bipolar Disorders (ISBD) conducted a systematic review on the efficacy and tolerability of ADHD medications in treating cognitive dysfunction in BD.<span><sup>2</sup></span></p><p>The review reassures on tolerability, concluding that when BD is properly stabilized, the risk of treatment-emergent manic episodes due to the use of stimulant or non-stimulant ADHD medications is not higher than with placebo or other control conditions. Thus, methylphenidate, lisdexamfetamine, armodafinil, modafinil or bupropion can be safely employed unless BD is pharmacologically stabilized. Beyond the reviewed evidence coming from Randomized Controlled Trials, a large Swedish registry study on 2307 adults with BD who later initiated methylphenidate for concurrent ADHD found no evidence for an association between methylphenidate and treatment-emergent mania among those on concomitant mood stabilizers. On the other hand, those treated with the stimulant alone had a 6.7 times increased rate of manic episodes within 3 months of medication initiation.<span><sup>3</sup></span> Hence, we might say that there is sufficient evidence not to discourage the use of ADHD medications in adequately stabilized BD.</p><p>However, the most compelling research aim was to review the efficacy of ADHD medications as cognitive enhancers in BD: the authors, based on evidence coming from three studies, concluded that there is insufficient data to assert that ADHD medications can improve cognition in BD. The first reviewed study was designed to assess the efficacy of adjunctive methylphenidate in reducing manic symptoms in acutely manic subjects. For safety reasons, the study lasted 2.5 days, after which methylphenidate was deemed ineffective and therefore stopped. The very short period of observation likely speaks for the observed lack of cognitive effect of methylphenidate. The second study, which evaluated the pro-cognitive effects of clonidine on manic subj","PeriodicalId":8959,"journal":{"name":"Bipolar Disorders","volume":"26 6","pages":"620-621"},"PeriodicalIF":5.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bdi.13459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>We read with interest the study by McIntyre et al. “Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder”<span><sup>1</sup></span> concluding that cariprazine was not superior to placebo in relapse prevention. However, based on our clinical experience successfully utilizing cariprazine to treat acute depressive, manic, and mixed episodes of bipolar I disorder, we have also found cariprazine helpful in preventing recurrence for the vast majority of patients who have remained on cariprazine over the past decade, when the dosing regimen is individualized to meet their needs.<span><sup>2</sup></span> Unfortunately, this was not the case for this study protocol, which may have contributed to an incorrect conclusion.</p><p>As a partial dopamine agonist with eightfold greater affinity for D3 than D2 receptors, and higher D3 affinity than one's endogenous dopamine,<span><sup>3</sup></span> cariprazine is a dynamic medication whereby finding the correct dose is critical to optimizing effects and minimizing side effects. Lower doses function as a dopamine agonist such that 1.5 mg daily can rapidly improve bipolar I depression within 2 weeks.<span><sup>3</sup></span> In contrast, higher approved doses, such as 4.5 mg and 6 mg, which function as a dopamine antagonist, may be required for rapid control of mania and psychosis over several days.<span><sup>3</sup></span> At times, patients who are stable on 1.5 mg cannot tolerate 3 mg due to akathisia. The 3 mg dose lies somewhere in between; it may be too dopamine blocking for some depressed patients yet insufficient for control of mania and psychosis. The unique pharmacodynamic features of cariprazine allow the prescriber to dial in the precise dose to meet patients' needs: lower doses for bipolar I depression; higher doses for bipolar mania and mixed episodes, potentially achieving full spectrum coverage as a relatively well-tolerated monotherapy.</p><p>Another unique aspect of cariprazine is the exceedingly long half-life of its active metabolites, and the protracted time to reach a steady state, which can surpass 12 weeks.<span><sup>3</sup></span> Occasionally, dose reduction is appropriate for late-occurring side effects, such as insomnia. It can also take up to 12 weeks following discontinuation for total cariprazine metabolites to become undetectable, and even longer for poor 3A4 metabolizers or for those taking 3A4 inhibitors,<span><sup>3</sup></span> such as cannabis (permitted in this study). This feature enables effective intermittent dosing schedules for those who either cannot tolerate daily dosing,<span><sup>3</sup></span> prefer intermittent dosing, or face challenges with adherence. Unlike many other antipsychotics, we do not typically encounter withdrawal effects with cariprazine due to low binding affinities for acetylcholine and histamine.<span><sup>3</sup></span> In our experience, bipolar I disorder patients who have taken cariprazine
我们饶有兴趣地阅读了麦金太尔(McIntyre)等人的研究报告:"卡哌嗪作为一种维持疗法,用于预防成人双相情感障碍 I 的情绪发作 "1 ,结论是卡哌嗪在预防复发方面并不优于安慰剂。然而,根据我们成功使用卡哌嗪治疗双相情感障碍 I 急性抑郁、躁狂和混合发作的临床经验,我们也发现卡哌嗪在预防复发方面很有帮助。作为一种部分多巴胺激动剂,它对 D3 受体的亲和力是 D2 受体的八倍,D3 受体的亲和力高于内源性多巴胺3 ,因此卡培拉嗪是一种动态药物,找到正确的剂量对于优化疗效和减少副作用至关重要。3 相反,4.5 毫克和 6 毫克等批准剂量较高的药物具有多巴胺拮抗剂的作用,可以在数天内迅速控制躁狂症和精神病。3 毫克的剂量介于两者之间;对于某些抑郁症患者来说,它的多巴胺阻断作用可能过强,但又不足以控制躁狂症和精神病。卡培拉嗪独特的药效学特征使处方者可以根据患者的需要调整精确的剂量:双相抑郁 I 期患者可使用较低剂量;双相躁狂症和混合发作患者可使用较高剂量,作为一种耐受性相对较好的单一疗法,卡培拉嗪有可能实现全方位治疗。3 有时,对于晚期出现的副作用,如失眠,可适当减少剂量。此外,停药 12 周后才能检测不到卡哌嗪的总代谢物,对于 3A4 代谢较差或服用 3A4 抑制剂(如大麻(本研究允许))的患者来说,这段时间甚至更长。对于那些不能耐受每日服药、3 偏爱间歇服药或在服药依从性方面面临挑战的患者来说,这一特点可以实现有效的间歇服药计划。与许多其他抗精神病药物不同,由于卡培拉嗪与乙酰胆碱和组胺的结合亲和力较低,我们通常不会遇到停药效应。3 根据我们的经验,服用卡培拉嗪数月的躁郁症患者在停药后的数月内可能会保持稳定,这是因为卡培拉嗪具有长效作用。3 在这一阶段,导致停药的不良事件(67 例)可能归因于这种激进的用药计划。相反,为什么不允许双相 I 型躁狂症和混合型患者按照 FDA 指南服用 4.5 毫克或 6 毫克?3 在这一阶段,因疗效不佳而停药的比例(35)可能归因于治疗剂量不足。未能达到随机化标准(143 例)也可能反映出缺乏个体化用药。半数以上的开放标签患者在双盲随机化之前停药,这限制了样本对那些服用 3 毫克疗效最好的患者的普适性,这就引出了下一个问题:为什么要把剂量降到 1.5 毫克?更有效的设计应该是根据指数发作情况进行剂量滴定,并在双盲阶段进行调整,以解决复发的早期迹象和/或耐受性问题,口服4 和长效注射阿立哌唑5 的双相 I 型维持治疗研究就是这样设计的。此外,卡哌嗪代谢物的作用时间比口服阿立哌唑的作用时间更长,后者的维持治疗研究时间为 74 周,为什么仅在 39 周后就停止研究呢?卡普兰-梅耶曲线在 36 周时开始出现分叉,包括复发时间和躁狂复发时间,这可能反映了躁狂症所需的卡哌嗪剂量较高,而抑郁症的药效学效应则较低。从现实世界的临床背景来看,这项研究同样可以得出结论:服用 3 毫克卡哌嗪 16 周,可以持久预防双相情感障碍 I 的抑郁、躁狂和混合发作的复发,其效果与剂量减至 1.5 毫克、继续服用 3 毫克或停药 39 周的效果相当,"所有症状和功能的改善均得以维持"。
{"title":"Revisiting cariprazine for bipolar I disorder maintenance treatment","authors":"Maxwell Z. Price, Richard L. Price","doi":"10.1111/bdi.13453","DOIUrl":"10.1111/bdi.13453","url":null,"abstract":"<p>We read with interest the study by McIntyre et al. “Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder”<span><sup>1</sup></span> concluding that cariprazine was not superior to placebo in relapse prevention. However, based on our clinical experience successfully utilizing cariprazine to treat acute depressive, manic, and mixed episodes of bipolar I disorder, we have also found cariprazine helpful in preventing recurrence for the vast majority of patients who have remained on cariprazine over the past decade, when the dosing regimen is individualized to meet their needs.<span><sup>2</sup></span> Unfortunately, this was not the case for this study protocol, which may have contributed to an incorrect conclusion.</p><p>As a partial dopamine agonist with eightfold greater affinity for D3 than D2 receptors, and higher D3 affinity than one's endogenous dopamine,<span><sup>3</sup></span> cariprazine is a dynamic medication whereby finding the correct dose is critical to optimizing effects and minimizing side effects. Lower doses function as a dopamine agonist such that 1.5 mg daily can rapidly improve bipolar I depression within 2 weeks.<span><sup>3</sup></span> In contrast, higher approved doses, such as 4.5 mg and 6 mg, which function as a dopamine antagonist, may be required for rapid control of mania and psychosis over several days.<span><sup>3</sup></span> At times, patients who are stable on 1.5 mg cannot tolerate 3 mg due to akathisia. The 3 mg dose lies somewhere in between; it may be too dopamine blocking for some depressed patients yet insufficient for control of mania and psychosis. The unique pharmacodynamic features of cariprazine allow the prescriber to dial in the precise dose to meet patients' needs: lower doses for bipolar I depression; higher doses for bipolar mania and mixed episodes, potentially achieving full spectrum coverage as a relatively well-tolerated monotherapy.</p><p>Another unique aspect of cariprazine is the exceedingly long half-life of its active metabolites, and the protracted time to reach a steady state, which can surpass 12 weeks.<span><sup>3</sup></span> Occasionally, dose reduction is appropriate for late-occurring side effects, such as insomnia. It can also take up to 12 weeks following discontinuation for total cariprazine metabolites to become undetectable, and even longer for poor 3A4 metabolizers or for those taking 3A4 inhibitors,<span><sup>3</sup></span> such as cannabis (permitted in this study). This feature enables effective intermittent dosing schedules for those who either cannot tolerate daily dosing,<span><sup>3</sup></span> prefer intermittent dosing, or face challenges with adherence. Unlike many other antipsychotics, we do not typically encounter withdrawal effects with cariprazine due to low binding affinities for acetylcholine and histamine.<span><sup>3</sup></span> In our experience, bipolar I disorder patients who have taken cariprazine ","PeriodicalId":8959,"journal":{"name":"Bipolar Disorders","volume":"26 5","pages":"491-492"},"PeriodicalIF":5.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bdi.13453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}