Dr. Ron’s Research Review – March 25, 2020

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This week’s research review focuses on reserpine and depression.

Reserpine is derived from Rauwolfia serpentina, and was commonly used as an antihypertensive agent in the 1950s.
Reserpine is effective in reducing SBP roughly to the same degree as other first-line antihypertensive drugs. (Shamon and Perez, 2016)
For five decades it has been generally accepted that reserpine, an antihypertensive and antipsychotic drug, causes depression. The discovery that reserpine depletes brain monoamines was an important factor in the development of the monoamine hypothesis of depression, and it continues to be widely cited in support of this hypothesis. A review argues that, contrary to prevailing belief, reserpine is not depressogenic. (Lobay, 2015) (Baumeister et al., 2003)

Reserpine is currently used by millions of Chinese hypertensive patients, in spite of the continued concern of its depressogenic effect, even when used in low dose.
A study investigated the association between low-dose reserpine use and depression in older Chinese hypertensive patient.
A cross-sectional, case-control study recruited patient aged 60 years or over who had regularly taken one or two tables of "compound reserpine and triamterene tablets (CRTTs)" for more than one year (reserpine user) from 26 community health centers located in 10 provinces in China. For each patient who took CRTTs, we selected an age (within five years) and sex matched hypertensive patient who had never taken any drugs containing reserpine (non-reserpine user) as control. Depressive symptoms were evaluated using a Chinese depression scale adapted from the Zung Self-Rating Depression Scale. Demographic, clinical data and laboratory examination results within six months were collected.
787 reserpine user and 787 non-reserpine user were recruited. The mean age of all study subjects was 70.3 years, with about equal numbers of males and females. The mean depression score was 40.4 in reserpine users and 40.6 in non-reserpine users (P = 0.7). The majority of study subject had a depression score < 53 (87.6% in reserpine users and 88.2% in non-reserpine users, respectively). There were no significant differences in the prevalence of mild, moderate or severe depression in reserpine users and non-reserpine users.
This study found no association between low-dose reserpine use and depression in older hypertensive patient. The role of reserpine in the treatment and control of hypertension should be reconsidered. (Zhu et al., 2019)

 

Dr. Ron

 


Articles

 

The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis.
(Baumeister et al., 2003) Download
For five decades it has been generally accepted that reserpine, an antihypertensive and antipsychotic drug, causes depression. The discovery that reserpine depletes brain monoamines was an important factor in the development of the monoamine hypothesis of depression, and it continues to be widely cited in support of this hypothesis. The present paper argues that, contrary to prevailing belief, reserpine is not depressogenic. The reason for perpetuation of this myth is reluctance to discard the monoamine hypothesis. This hypothesis ushered the modern biochemical paradigm into psychiatry and is still of great importance. It serves as a heuristic to guide research, it enhances psychiatry's prestige, and it helps to validate and promote drug therapy for depression and other mental disorders.

Rauwolfia in the Treatment of Hypertension.
            (Lobay, 2015) Download
Rauwolfia serpentina is a safe and effective treatment for hypertension. The plant was used by many physicians throughout India in the 1940s and then was used throughout the world in the 1950s, including in the United States and Canada. It fell out of popularity when adverse side effects, including depression and cancer, became associated with it. This author reviews the scientific literature with regard to the use of Rauwolfia and the treatment of hypertension. The author reviews the plant's botany, chemistry, and pharmacology and provides a researched and documented method of action for the active ingredients. With special emphasis on the plant's role in treating high blood pressure, the author looks at medical uses of the plant, critically examining its adverse side effects, toxicology, and carcinogenicity. The author refutes the association between the plant and carcinogenicity and discusses the importance of correct dosing and of screening patients to minimize the occurrence of depression. He concludes with the recommendation of use of low dose Rauwolfia (LDR) for suitable patients with hypertension. The plant provides clinicians with a safe and effective adjunct to pharmaceuticals in the treatment of high blood pressure.


 

Blood pressure-lowering efficacy of reserpine for primary hypertension.
            (Shamon and Perez, 2016) Download
BACKGROUND:  Many antihypertensive agents exist today for the treatment of primary hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, or both). Randomised controlled trials (RCTs) have been carried out to investigate the evidence for these agents. There is, for example, strong RCT evidence that thiazides reduce mortality and morbidity. Some of those trials used reserpine as a second-line therapy. However, the dose-related blood pressure reduction with this agent is not known. OBJECTIVES:  The primary objective of this review was to quantify the dose-related efficacy of reserpine versus placebo or no treatment in reducing systolic blood pressure (SBP) or diastolic blood pressure (DBP), or both.We also aimed to evaluate the dose-related effects of reserpine on mean arterial blood pressure (MAP) and heart rate (HR), as well as the dose-related effects on withdrawals due to adverse events. SEARCH METHODS:  We searched the Cochrane Hypertension Group Specialised Register (January 1946 to October 2016), CENTRAL (2016, Issue 10), MEDLINE (January 1946 to October 2016), Embase (January 1974 to October 2016), and ClinicalTrials.gov (all dates to October 2016). We also traced citations in the reference sections of the retrieved studies. SELECTION CRITERIA:  Included studies were truly randomised controlled trials (RCTs) comparing reserpine monotherapy to placebo or no treatment in participants with primary hypertension. DATA COLLECTION AND ANALYSIS:  We assessed methods of randomisation and concealment. We extracted and analysed data on blood pressure reduction, heart rate, and withdrawal due to adverse effects. MAIN RESULTS:  We found four RCTs (with a total of 237 participants) that met the inclusion criteria, none of which we found through the 2016 update search. The overall pooled effect demonstrates a statistically significant systolic blood pressure (SBP) reduction in participants taking reserpine compared with placebo (weighted mean difference (WMD) -7.92, 95% confidence interval (CI) -14.05 to -1.78). Because of significant heterogeneity across the trials, a significant effect in diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) could not be found. A dose of reserpine 0.5 mg/day or greater achieved the SBP effects. However, we could not determine the dose-response pattern because of the small number of trials. We did not combine data from the trial that investigated Rauwiloid against placebo with reserpine data from the remaining three trials. This is because Rauwiloid is a different alkaloid extract of the plant Rauwolfia serpentina, and the dose used is not comparable to reserpine. None of the included trials reported withdrawals due to adverse effects. AUTHORS' CONCLUSIONS:  Reserpine is effective in reducing SBP roughly to the same degree as other first-line antihypertensive drugs. However, we could not make definite conclusions regarding the dose-response pattern because of the small number of included trials. More RCTs are needed to assess the effects of reserpine on blood pressure and to determine the dose-related safety profile before the role of this drug in the treatment of primary hypertension can be established.


No association between low-dose reserpine use and depression in older hypertensive patient: result of a multicenter, cross-sectional study.
            (Zhu et al., 2019) Download
Background:  Reserpine is currently used by millions of Chinese hypertensive patients, in spite of the continued concern of its depressogenic effect, even when used in low dose. This study aimed to investigate the association between low-dose reserpine use and depression in older Chinese hypertensive patient. Methods:  In this cross-sectional, case-control study, we recruited patient aged 60 years or over who had regularly taken one or two tables of "compound reserpine and triamterene tablets (CRTTs)" for more than one year (reserpine user) from 26 community health centers located in 10 provinces in China. For each patient who took CRTTs, we selected an age (within five years) and sex matched hypertensive patient who had never taken any drugs containing reserpine (non-reserpine user) as control. Depressive symptoms were evaluated using a Chinese depression scale adapted from the Zung Self-Rating Depression Scale. Demographic, clinical data and laboratory examination results within six months were collected. Results:  From August 2018 to December 2018, 787 reserpine user and 787 non-reserpine user were recruited. The mean age of all study subjects was 70.3 years, with about equal numbers of males and females. The mean depression score was 40.4 in reserpine users and 40.6 in non-reserpine users ( Conclusions:  There is no association between low-dose reserpine use and depression in older hypertensive patient. The role of reserpine in the treatment and control of hypertension should be reconsidered; and further studies, especially randomized, controlled clinical trials to compare efficacy and safety of reserpine and other widely recommended anti-hypertensive agents are needed.

 

References

Baumeister, AA, MF Hawkins, and SM Uzelac (2003), ‘The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis.’, J Hist Neurosci, 12 (2), 207-20. PubMed: 12953623
Lobay, D (2015), ‘Rauwolfia in the Treatment of Hypertension.’, Integr Med (Encinitas), 14 (3), 40-46. PubMed: 26770146
Shamon, SD and MI Perez (2016), ‘Blood pressure-lowering efficacy of reserpine for primary hypertension.’, Cochrane Database Syst Rev, 12 CD007655. PubMed: 27997978
Zhu, GH, et al. (2019), ‘No association between low-dose reserpine use and depression in older hypertensive patient: result of a multicenter, cross-sectional study.’, J Geriatr Cardiol, 16 (8), 608-13. PubMed: 31555328