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Mitochondrial modulators in the treatment of bipolar depression: a systematic review and meta-analysis

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• Published: 10 January 2022

Mitochondrial modulators in the treatment of bipolar depression: a systematic review and meta-analysis

• Liang Liang, 
• Junyu Chen, 
• Ling Xiao, 
• Qing Wang & 
• Gaohua Wang 

Translational Psychiatry volume 12, Article number: 4 (2022) Cite this article

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Abstract

Mitochondrial dysfunction has been implicated in the risk, pathophysiology, and progression of mood disorders, especially bipolar disorder (BD). Thus, the objective of this meta-analysis was to determine the overall antidepressant effect of mitochondrial modulators in the treatment of bipolar depression. Outcomes included improvement in depression scale scores, Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity Scale (CGI-S) score. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of diverse mitochondrial modulators were pooled to determine standard mean differences (SMDs) compared with placebo.13 RCTs were identified for qualitative review. The overall effect size of mitochondrial modulators on depressive symptoms was −0.48 (95% CI: −0.83 to −0.14, p = 0.007, I2 = 75%), indicative of a statistically significant moderate antidepressant effect. In the subgroup analysis, NAC improved depressive symptoms compared with placebo (−0.88, 95% CI: −1.48 to −0.27, I2 = 81%). In addition, there was no statistical difference between mitochondrial modulators and placebo in YMRS. Although mitochondrial modulators were superior to placebo in CGI-S score (−0.44, 95% CI: −0.83 to −0.06, I2 = 71%), only EPA was superior to placebo in subgroup analysis. Overall, a moderate antidepressant effect was observed for mitochondrial modulators compared with placebo in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.

초록

미토콘드리아 기능 장애는

기분 장애, 특히 양극성 장애(BD)의 위험, 병태생리 및 진행과 관련이 있습니다.

따라서 이 메타 분석의 목적은

양극성 우울증 치료에서

미토콘드리아 조절제의 전반적인 항우울 효과를 결정하는 것이었습니다.

결과에는

우울증 척도 점수, 영 조증 평가 척도(YMRS) 및 임상 전반 인상-중증도 척도(CGI-S) 점수의 개선이 포함되었습니다.

다양한 미토콘드리아 조절제의 항우울 효과를 평가한 무작위 대조 시험(RCT)의 데이터는 위약과 비교하여 표준화된 평균 차이(SMD)를 결정하기 위해 통합되었습니다. 질적 검토를 위해 13개의 RCT가 식별되었습니다. 우울 증상에 대한 미토콘드리아 조절제의 전반적인 효과 크기는 -0.48 (95% CI: -0.83 ~ -0.14, p = 0.007, I2 = 75%)이었으며, 이는 통계적으로 유의미한 중간 정도의 항우울 효과를 나타냅니다. 하위 그룹 분석에서 NAC는 위약에 비해 우울 증상을 개선했습니다(-0.88, 95% CI: -1.48 ~ -0.27, I2 = 81%). 또한, YMRS에서는 미토콘드리아 조절제와 위약 사이에 통계적 차이가 없었습니다. 미토콘드리아 조절제가 CGI-S 점수에서 위약보다 우수했지만(-0.44, 95% CI: -0.83 ~ -0.06, I2 = 71%), 하위 그룹 분석에서는 EPA만이 위약보다 우수했습니다.

전반적으로,

양극성 우울증 치료에서 미토콘드리아 조절제는

위약에 비해 중간 정도의 항우울 효과를 보였습니다.

연구 수가 적고, 약물의 다양성 및 적은 표본 크기가 현재 분석의 해석을 제한했습니다.

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Introduction

Bipolar disorder (BD) is a common mood disorder characterized by alternating manic and depressive episodes [1]. Previous study reported that patients with bipolar depression are four times more likely to commit suicide compared to the general population [2]. Current psychopharmacological therapies are often insufficient, and about 40% of people with BD do not adhere to their prescribed treatment [3]. Therefore, there is an urgent need to elucidate novel targets that may yield improved efficacy and prevent subsequent mood episodes.

Although antidepressants may be used in combination with mood stabilizers or second-generation antipsychotics for bipolar depression, the treatment of BD is still particularly challenging because of the high non-responder rate. One treatment avenue currently being explored is the adjunctive use of mitochondrial modulators [4]. Several studies showed that mitochondrial dysfunction and oxidative stress may be involved in the development and progression of BD [5,6,7]. Mitochondria regulate energy production and generation of adenosine-5′-triphosphate (ATP) through the mitochondrial electron transport chain (ETC). Furthermore, they also regulate calcium and apoptotic processes and are central to facilitating neuronal plasticity. Therefore, dysfunctional mitochondria can result in neuronal damage via multiple mechanisms. At present, there are N-acetyl-cysteine (NAC), acetyl-l-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), vitamin D, and melatonin exist for treating bipolar depression [4, 8]. In the last few decades, substantial efforts have been made to eval‎uate the efficacy of mitochondrial modulators for the treatment of bipolar depression, both in monotherapy and as adjunctive treatment [9,10,11,12,13,14,15,16,17,18,19,20,21]. However, it remains unclear whether mitochondrial modulators has any benefit for the treatment of depressive symptoms in patients with mood disorders. For example, Kishi’s meta-analysis reported that N-acetylcysteine decreased CGI-S score, but no specific improvements in depressive symptoms [22]. However, Rosenblat’s meta-analysis showed that a moderate antidepressant effect was observed for adjunctive N-acetylcysteine in patients with mood disorders [23]. In addition, other mitochondrial regulators are also controversial in the treatment of depressive symptoms.

This meta-analysis was conducted to examine efficacy of mitochondrial modulators for the treatment of BDs in patients with depressive symptoms.

서론

양극성 장애(BD)는

조증 삽화와 우울 삽화가 교대로 나타나는 것을 특징으로 하는

흔한 기분 장애입니다 [1].

이전 연구에 따르면 양극성 우울증 환자는

일반 인구에 비해 자살 위험이 4배 더 높습니다 [2].

현재의 정신약물학적 치료는 종종 불충분하며,

BD 환자의 약 40%는 처방된 치료를 따르지 않습니다 [3].

따라서

효능을 개선하고 후속 기분 삽화를 예방할 수 있는

새로운 표적을 규명할 시급한 필요성이 있습니다.

항우울제가 양극성 우울증에 대해 기분 안정제 또는 2세대 항정신병 약물과 병용될 수 있지만,

높은 무반응률 때문에 BD 치료는 여전히 특히 어렵습니다.

현재 탐색되고 있는 한 가지 치료 방법은

미토콘드리아 조절제의 보조적 사용입니다 [4].

여러 연구에서

미토콘드리아 기능 장애와 산화 스트레스가

BD의 발병 및 진행에 관여할 수 있음을 보여주었습니다 [5,6,7].

미토콘드리아는

미토콘드리아 전자 전달 사슬(ETC)을 통해

에너지 생산 및 아데노신-5'-삼인산(ATP) 생성을 조절합니다.

또한,

칼슘 및 세포자멸사 과정을 조절하며

신경 가소성을 촉진하는 데 핵심적인 역할을 합니다.

따라서

기능 장애가 있는 미토콘드리아는

여러 메커니즘을 통해 신경 손상을 초래할 수 있습니다.

현재, 양극성 우울증 치료를 위해

N-아세틸시스테인(NAC),

아세틸-L-카르니틴(ALCAR),

S-아데노실메티오닌(SAMe),

코엔자임 Q10(CoQ10),

알파-리포산(ALA),

크레아틴 모노하이드레이트(CM),

비타민 D 및 멜라토닌이 존재합니다 [4, 8].

지난 수십 년 동안,

단독 요법 및 보조 치료로서 양극성 우울증 치료를 위한

미토콘드리아 조절제의 효능을 평가하기 위해 상당한 노력이 이루어졌습니다

[9,10,11,12,13,14,15,16,17,18,19,20,21].

그러나 미토콘드리아 조절제가 기분 장애 환자의 우울 증상 치료에 어떤 이점이 있는지는 여전히 불분명합니다. 예를 들어, Kishi의 메타 분석은 N-아세틸시스테인이 CGI-S 점수를 감소시켰지만, 우울 증상에는 특별한 개선이 없었다고 보고했습니다 [22]. 그러나 Rosenblat의 메타 분석은 기분 장애 환자에서 보조 N-아세틸시스테인의 중간 정도의 항우울 효과가 관찰되었다고 보여주었습니다 [23]. 또한, 다른 미토콘드리아 조절제도 우울 증상 치료에 있어 논란의 여지가 있습니다.

이 메타 분석은 우울 증상이 있는 BD 환자에서 미토콘드리아 조절제의 효능을 검토하기 위해 수행되었습니다.

Methods

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [24].

Search methods for identification of trials

Two authors independently identified eligible studies indexed in the PubMed, MEDLINE, Cochrane, and Embase databases published in any language from the inception of the study to October 25, 2020. The search terms included (bipolar depression or BD) and (N-acetylcysteine or omega-3 polyunsaturated fatty acids or inositol or CoQ10 or ALA or CM or vitamin D). The authors also searched ClinicalTrials.gov (http://clinicaltrials.gov/) to ensure a comprehensive search. The reference lists of the retrieved publications were searched manually for additional relevant studies. All identified articles were screened by two independent reviewers for inclusion in qualitative and quantitative analysis. Where there was disagreement on inclusion, the consensus was reached through discussion.

Inclusion criteria

Inclusion criteria are as follows: (1) participants over the age of 18 years; (2) DSM or ICD diagnosis of bipolar I disorder (BD-I), bipolar II (BD-II) disorder or BD not otherwise specified (BD-NOS); (3) RCTs of mitochondrial modulators compared with placebo; (4) depression severity assessed and reported using Montgomery and Asberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HDRS). The authors were contacted for data not provided in the papers. If the authors could not provide the necessary data, the trial was excluded from the quantitative analysis.

Data extraction and statistical analysis

Two authors performed independently to identify RCTs that met the inclusion criteria and then data (including study characteristics, risks of bias, and depression severity scores) were extracted from included studies. Changes in depression severity scores (MADRS and HDRS), Young Mania Rating Scale (YMRS) scores, and Clinical Global Impression-Severity Scale (CGI-S) scores of mitochondrial modulators treatment versus placebo were used in the analysis. A prespecified p-value of 0.05 was set to determine the presence of a statistically significant reduction in depression severity. To further eval‎uate the eligibility of potential studies, we discussed any disagreements with another author.

The meta-analysis was performed using the RevMan version 5.3. Continuous outcomes were analyzed by calculating the SMDs with 95% CIs. Pooled effect sizes were subgrouped based on the mitochondrial modulator tested and then pooled to calculate the overall effect size of all mitochondrial modulators included. The statistical heterogeneity and inconsistency in treatment effects across studies were eval‎uated using Cochran’s Q test and I2 statistics, respectively. Heterogeneity was quantified using the I2 statistic, where 25% = small, 50% = moderate, and 75% = high heterogeneity [25]. Statistical significance was defined as p < 0.05.

Assessment of bias

The risk of bias was assessed using the tool recommended by the Cochrane Handbook for systematic reviews of randomized trials. The risks of selection bias, performance bias, detection bias, attrition bias, reporting bias and other biases were independently examined by two reviewers and categorized as low risk, high risk, or unclear risk. The risk of bias was designated to be high if described protocols were concerning for bias in a given domain or if the description of the domain was omitted from the primary text. In addition, to assess for publication bias, a funnel plot was created using Review Manager 5.3 Software.

Results

Search results

A total of 3017 records were identified, 2976 through database searches, and 41 through other sources. Of these articles, 1403 were deemed ineligible after thoroughly screening their titles and abstracts. The remaining 268 studies underwent a full-text eval‎uation to further eval‎uate their eligibility in which 255 articles were excluded because they did not meet the inclusion criteria. Ultimately, a total of 13 studies were included in this meta-analysis, including four RCTs of N-acetylcysteine (NAC) [9,10,11,12], three RCTs of Omega-3 polyunsaturated fatty acids (EPA) [13,14,15], one RCT of Coenzyme Q10 (CoQ10) [16], one RCT of CM [17], one RCT of Vitamin D [20], two RCTs of Inositol [18, 19], and one RCT of ALCAR+ALA [21] (Fig. 1). Table 1 shows the characteristics of each study and the characteristics of patients included in each study.

Fig. 1: PRISMA flow diagram.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study selection flow diagram.

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Table 1 Summary of study characteristics, demographics and treatment characteristics of the double-blinded, randomized, placebo-controlled trials.

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Assessment of bias

Included studies were assessed for bias in seven domains—namely, random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other biases. The results are summarized in Table 2. All included studies were assessed independently by two authors, and the risk of bias for each item was categorized as ‘low risk’, ‘unclear’ or ‘high risk’. Publication bias was assessed using a funnel plot, as shown in Fig. 2.

Table 2 Assessment of risk of bias.

Full size table

Fig. 2: Funnel plot for publication bias.

Begg’s funnel plot for publication bias analysis.

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Change in depression severity scores

The pooled effect size was based on a total of 605 participants, including studies assessing NAC (n = 292), EPA (n = 102), CoQ10 (n = 69), CM (n = 27), vitamin D (n = 33), Inositol (n = 42), ALCAR+ALA (n = 40). As shown in Fig. 3, the overall SMD of mitochondrial modulators compared with placebo was −0.48 (95% CI: −0.83 to −0.14, p = 0.007, I2 = 75%), indicative of a statistically significant moderate antidepressant effect. In the subgroup analysis, four RCTs assessed the antidepressant effects of NAC in patients with BD. The results showed an SMD of −0.88 (95% CI: −1.48 to −0.27, I2 = 81%). Three studies using EPA in the treatment of BD were identified. Pooling of effect sizes for these studies revealed an SMD of −0.47 (95% CI: −1.03 to 0.09, I2 = 45%), indicative of no statistical difference between EPA and placebo. Two studies using inositol in the treatment of BD were identified. The calculated effect size was 0.01 (95% CI: −0.63 to 0.66, I2 = 11%), indicative of no statistical difference between inositol and placebo. One RCT investigating the effect of CoQ10 was identified. A significantly greater reduction in MADRS scores was observed in the CoQ10 group compared with the placebo group. However, there were no statistically significant differences observed in the CM and ALCAR+ALA groups compared with the placebo. In addition, one notable trial assessed the antidepressant effect of vitamin D was negative for this study.

Fig. 3: Forest plot of pooled effect sizes of mitochondrial modulators for bipolar depression.

CoQ10 Coenzyme Q10, CM creatine monohydrate, EPA eicosapentaenoic acid, NAC N-acetylcysteine, SD standard deviation, SMD standard mean difference.

Full size image

Change in YMRS

The pooled effect size of YMRS was based on a total of 478 including studies assessing NAC (n = 292), EPA (n = 102), CM (n = 27), Inositol (n = 17), ALCAR + ALA (n = 40). As shown in Fig. 4, the overall SMD of mitochondrial modulators compared with placebo was −0.04 (95% CI: −0.39 to 0.31, I2 = 69%), indicative of no statistical difference between mitochondrial modulators and placebo. In addition, there were no differences in the results of each subgroup analysis.

Fig. 4: Forest plots for YMRS reductions with mitochondrial modulators.

CM creatine monohydrate, EPA eicosapentaenoic acid, NAC N-acetylcysteine, SD standard deviation, SMD standard mean difference.

Full size image

Change in CGI-S

The pooled effect size of CGI-S was based on a total of 423 including studies assessing NAC (n = 275), EPA (n = 81), CM (n = 27), ALCAR + ALA (n = 40). For the CGI-S, the overall SMD of mitochondrial modulators compared with placebo was −0.44 (95% CI: −0.83 to −0.06, I2 = 71%), indicative of a statistically significant difference. In the subgroup analysis, only EPA was superior to placebo in CGI-S (−1.07, 95% CI: −2.03 to −0.11, I2 = 73%) (Fig. 5).

Fig. 5: Forest plots for CGI-S reductions with mitochondrial modulators.

CM creatine monohydrate, EPA eicosapentaenoic acid, NAC N-acetylcysteine, SD standard deviation, SMD standard mean difference.

Full size image

Discussion

To our knowledge, this is the first systematic review to eval‎uate the efficacy of mitochondrial modulators in the treatment of bipolar depression. This analysis suggests that mitochondrial modulators have a significant antidepressant effect in BD when compared with placebo (as measured by the change in depressive symptom severity). In this study, the overall effect size was found to be moderate (SMD = −0.48), and comparable with the antidepressant effect size of quetiapine (SMD = −0.29), lurasidone (SMD = −0.36), olanzapine (SMD = −0.52), as indicated by a previous meta-analysis [26]. Our results also showed that no significant change between each drug in YMRS. In addition, the results highlighted that mitochondrial modulators decreased CGI-S scores (assessing overall disease severity in patients) compared with the placebo.

논의

저희가 아는 한, 이 연구는

양극성 우울증 치료에서

미토콘드리아 조절제의 효능을 평가한 최초의 체계적인 검토입니다.

이 분석은 위약과 비교했을 때(우울 증상 심각도 변화로 측정),

미토콘드리아 조절제가 양극성 장애(BD)에서 상당한 항우울 효과를 가지고 있음을 시사합니다. 

본 연구에서 전반적인 효과 크기는 중간 정도(SMD = -0.48)로 나타났으며,

이전 메타 분석에서 보고된

쿠에티아핀(SMD = -0.29), 루라시돈(SMD = -0.36), 올란자핀(SMD = -0.52)의

항우울 효과 크기와 비슷했습니다 [26]. 

또한, 저희 결과는 YMRS에서 각 약물 간에 유의미한 변화가 없음을 보여주었습니다. 또한, 이 결과는 미토콘드리아 조절제가 위약과 비교하여 CGI-S 점수(환자의 전반적인 질병 심각도 평가)를 감소시켰음을 강조했습니다.

Subgroup analysis of EPA, CM, inositol, ALCAR+ALA, and vitamin D underpowered, revealed effect sizes that were not statistically significant. Only NAC and CoQ10 were found to have a statistically significant antidepressant effect; however, the effect analysis of CoQ10 was based only on a single study, rather than a pooled sample. Our finding was consistent with a meta-analysis of NAC in depression by Fernandes et al. [27]. However, another study did not support the use of N-acetylcysteine as an adjunct to usual treatment for patients with depressive symptoms [22]. In summary, this study suggests that mitochondrial modulators may have antidepressant properties in BD, although statistical significance was only reached when pooling the effects of all mechanistically dissimilar agents together.

EPA, CM, 이노시톨, ALCAR+ALA, 비타민 D의 하위 그룹 분석은 통계적으로 유의미하지 않은 효과 크기를 나타냈으며, 이는 통계적 검정력이 부족했기 때문입니다. NAC와 CoQ10만이 통계적으로 유의미한 항우울 효과를 보였지만, CoQ10의 효과 분석은 통합된 표본이 아닌 단일 연구에만 기반했습니다. 저희의 결과는 Fernandes 등 [27]의 우울증에서 NAC에 대한 메타 분석과 일치했습니다. 그러나 다른 연구는 우울 증상이 있는 환자에게 N-아세틸시스테인을 일반적인 치료에 보조적으로 사용하는 것을 지지하지 않았습니다 [22]. 요약하면, 이 연구는 미토콘드리아 조절제가 BD에서 항우울 특성을 가질 수 있음을 시사하지만, 모든 기계적으로 다른 약물의 효과를 함께 통합했을 때만 통계적 유의미성에 도달했습니다.

이 연구에는 몇 가지 한계가 있습니다. 첫째, 이 메타 분석에는 연구 수가 제한적이었고 표본 크기가 작았습니다. 1차 결과 및 기타 요인과 관련된 연관성은 발견되지 않았습니다. 모든 민감도 분석에서도 I2 값이 50% 미만으로 감소하지 않았습니다. 따라서 1차 결과의 상당한 이질성에 대한 어떠한 이유도 감지하지 못했습니다. 두 번째 한계는 우울증 점수 변화에 대한 보고가 불충분하여 멜라토닌을 평가한 두 연구를 정량적 분석에서 제외한 것입니다. BD에서 미토콘드리아 조절제의 항우울 효과에 대한 광범위한 평가가 완료되었지만, BD 치료에서 멜라토닌의 효과를 평가한 다른 연구는 부족합니다. 또한, 포함된 여러 연구에서 잠재적 편향의 존재는 현재 분석의 또 다른 한계입니다. 마지막으로, 포함된 모든 시험은 상대적으로 짧은 기간이었습니다. 미토콘드리아 조절제가 BD 환자의 우울 증상 재발을 예방할 수 있는지 여부를 조사하기 위해서는 장기 연구가 추가적으로 필요합니다.

This study has certain limitations. First, there was a limited number of studies and small sample sizes in this meta-analysis. No associations with respect to the primary outcome and other factors were found. All sensitivity analyses also showed no reduction in I2 values below 50%. Thus, we did not detect any reasons for considerable heterogeneity in the results of the primary outcome. The second limitation was the exclusion of two studies assessing melatonin from the quantitative analysis owing to inadequate reporting of the change in depression scores. While more extensively eval‎uating the antidepressant effects of mitochondrial modulators in BD has been completed, lacking other studies assessing the effects of melatonin in the treatment of BD. In addition, the presence of potential bias in several of the included studies presents another limitation of the current analysis. Finally, all included trials had a relatively short duration. Long-term studies are further needed to examine whether mitochondrial modulators can prevent the recurrence of depressive symptoms in patients with BD.

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