A Combinatorial Antihypertensive Drug (Reserpine and Hydrazine) Does Not Cause Severe Depression

Background and objectives: Reserpine, a traditional Indian Ayurvedic medicine, is approved by the FDA to treat hypertension and for treatment resistant psychosis. The major reported side effect of reserpine is depression. Hence, hypertensive patients on prolonged reserpine treatment were evaluated for occurrence of depression. Methods: One-time cross-sectional evaluation was done in 104 subjects on reserpine and 105 controls, who were matched for age (majority being between 50- 70 years old), sex, education, and social background. The Control group had no chronic disease and the treatment group comprised of hypertensive patients who had received reserpine as Adelphane (0.1mg reserpine and 10mg of hydralazine) or Adelphane Esidrex [Novaritis (Basel, Switzerland)] for more than 1 year. Both the groups were asked to answer (and were rated by) Hamilton Depression Rating Scale (HDRS-17-items version). The results were scored, statistically analyzed and plotted with Sigma Plot. Results : Results obtained by the HDRS were classified into normal, and different levels of depression by score-based categorization. Of the 105 control and 104 treated patients, 38% (both control and treated) were normal, 38% control and 48% treated had mild depression while 23.8% control and 13.4% treated had moderate depression. No severe or very severe depression in control or treated group was found. Interpretation and Conclusion: Reserpine does not cause depression even when taken for years. The study is small with ~100 subjects per group. As a proven antihypertensive drug, our results should pave the way to bring reserpine into the mainstream..


Introduction
Hypertension is one of the most common non-communicable chronic diseases. More than a billion people in the world are hypertensive [1]. Hypertension is a silent killer causing premature mortality [2]. Unlike other diseases, the risk for hypertension exists in all adults (starting from 25 years) and is frequent from middle age (40 years) [3]. Uncontrolled blood pressure leads to heart disease, stroke and kidney failure [4], causing untimely mortality and disability. Impairment of blood circulation in the brain can cause several neurological complications including cognitive impairment. In fact, vascular dementia is quite common. In addition, hypertension is disproportionally more prevalent in low-and middle-income countries [5]. Hence, an effective public health initiative to identify, control and treat hypertension is an urgent necessity. According to WHO [3], the prevalence of hypertension is around 40% in the low-, and middle-income countries, and ~34% in the Western countries, with a slightly lower rates in women (still >30%) all over the world [3]. Hence, effective diagnosis and treatment is a necessity. In a Chi nese rural population, more than 44% use a preparation of herbal compounds that contains reserpine [6].

Study design
Subjects: Age, sex, education and socioeconomic background matched control (not hypertensive) and hypertensive patients on Adelphane [11] or Adelphane Esidrex [12] from Novaritis, Basel, Switzerland for several years were recruited. The International Standard Sri Ramachandra University Institute Ethics Committee clearance was obtained before the study was initiated and patient consent was acquired. The control group (N=105) and the Adelphane (reserpine) treated group (N=104) were from the same locality. This was a blinded cross-sectional study. More than 80% patients were on the drug for more than one year while ~33% were taking the drug for more than 10 years. Around 1.4% were taking the reserpine-based drug for more than 18 years.

Period:
The study took almost one year to complete. The field visits and data collection took one year. Further, data consolidation and analysis took another six months. On the whole, it was started in May 2015 and ended in December 2016.
Hypertension treatment: The Kidney Help Trust of Chennai has been using reserpine as Adelphane (0.1mg reserpine and 10mg of hydralazine) [11] or Adelphane Esidrex (has 10mg of hydrochlorothiazide added to Adelphane) [12] manufactured and sold by Novaritis, Switzerland to treat hypertension in patients in 56 villages and hamlets around Chennai, India from 1995 onwards. The dosage varies from 1 tablet to 4 tablets per day depending upon the condition of the patient. The drug is very effective at the given dose for a very long period (in years) and is well tolerated by the patients.
Depression evaluation: Depression in both the groups, patients and controls, was evaluated using the Hamilton Depression Rating Scale-17 items version [24] and scored. Further, based on the scores they were categorized according to the severity of depression [25,26].
Statistical analysis: Statistical analysis of the scores obtained through the HDRS was done using Sigma Plot 10.0. Statistical significance was determined by Students t-test and Mann-Whitney Rank Sum Test.

Results
Control group (105) and patients receiving reserpine (104) were screened for depression with the Hamilton Depression Rating scale (17-items Version). The results obtained by the HDRS [24] were classified into normal and various levels of depression judged on the score-based categorization [25,26] (Table 1,2). Overall, there was no difference between the control and patients on reserpine (Figure 1). In the two groups, 38.09 % of control and 38.46% of treated patients were normal (Figure 2), while 38.09 % of control and 48.07% of treated had mild depression (Figure 3). 23.8% of control and 13.46% of treated belonged to moderate depression category ( Figure 4) ( Table 1,2). There was no one with severe or very severe depression in either control or treated of both genders. No significant difference was observed between the two groups. Of the approximately 2000 or so patients on reserpine under kidney help trust in Chennai, India, only three had been removed from reserpine, confirming that reserpine is an inexpensive and effective antihypertensive drug.

Discussion
Hypertension is one of the major non-communicable diseases of this age with the prevalence between 30-40%. Without any symptoms, it is a silent killer causing sudden deaths. Given the enormous prevalence, morbidity, mortality, social, financial and economic burden on mankind, it becomes imperative to address this problem on a war footing.
A major initiative is by the kidney help trust in Chennai, which has been screening rural population for diabetes and hypertension from 1995 onwards and providing treatment for persons with these diseases [4][5][6][7][8][9][10][11]. The antihypertensive drug used is Adelphane. This is the least expensive hypertensive medication and also the most effective, given that antihypertensive drugs need to be taken lifelong and cost is a major factor [4][5][6][7][8][9][10]. Hence, reserpine is the drug of choice for the poor [4][5][6][7][8][9][10][11]. One major concern about reserpine is the possibility of it causing severe depression. One of the major reasons for reserpine not being widely used is this alleged negative effect [15,23]. But, evidence-based reports are hard to find [21]. Even so, depression is reported only in the high doses used to treat psychosis. In mice studies, at a low dosage of 1mg/kg reserpine does not cause depression and the manic depression pathological marker mkb-1 is not induced, but at the dosage of 2mg/kg both these effects are noticed [27]. It is widely in use, especially as an antihypertensive drug, even at a community level on [4][5][6][7][8][9][10][11] the low dosage of 0.1mg-0.6mg against hypertension with minimal side effects for several years and it reduces mortality when used as an antihypertensive [28].
Depression in patients on long-term reserpine treatment for hypertension was evaluated with HDRS. Overall, there was no difference in the scores between control and patients on reserpine ( Figure 1A). Of the 105 control and 104 treated patients, 38% (both control and treated) were normal (Figure 2A), 38% of control and 48% of treated had mild depression ( Figure 3A) while 23.8% of control and 13.4% of treated had moderate depression ( Figure 4A). No one was found with severe or very severe depression in either control or treated group. Further, the profile did not show much difference either in the overall score level ( Figure 1B) or across the spectrum of normal ( Figure 2B), mild ( Figure 3B) and moderate ( Figure 4B) depression between males and females, though there were more females than males in both the control and treated cohorts. In order to reconfirm, around 50% of control and reserpine treated patients were retraced. While more than 80% of the patients were on reserpine for more than two years, 33% were taking reserpine for more than 10 years. Around 1.4% were taking reserpine for more than 18 years. The blood pressure of control subjects was normal while the Adelphane/Adelphane esidrex treated patients had been brought down by 10mm Hg in both diastolic and systolic blood pressure (Table 3). Contrary to the suspected implications, reserpine seems to be safe for prolonged usage as an antihypertensive. This is further iterated by the usage of reserpine in 44% of rural Chinese population as an herbal compound preparation [6]. Moreover, reserpine has always been considered to be an effective antihypertensive, even for older patients [29]. In a situation where the world is aging, life expectancy is increasing, majority of the patients on reserpine treatment are between 50 and 70 years old in the poor, rural Related to increased health span, it has been identified that reserpine could provide high quality lifespan extension in C. elegans [30,31]. In addition, reserpine was able to provide protection against dementia -Alzheimer disease (a geriatric disease affecting many old people, known to be a huge social and financial burden on society) causing, Aβ-induced toxicity manifested as progressive paralysis, in the C. elegans model [31][32][33]. Similarly, in the AD mouse model, Tg2576, expressing human mutant APP, which causes Aβ aggregates formation and cognitive deficits at ~11 months of age, reserpine reduces the Aβ levels [34] and enhances working memory [35] in the 5XFAD AD model [36]. Further, reserpine is protective against another fatal neurodegenerative disease, amyotrophic lateral sclerosis, again in the C. elegans model [37]. Thus, in the model organism C. elegans, better health span and protection against two neurodegenerative disease-causing proteins could be achieved.
Hence, given the large scale of the hypertension problem that the world is facing, reserpine-based treatment shows a way to treat the disease safely, effectively and in an inexpensive manner where cost is a huge constraint in the low and middle income countries. However, during the initiation period, the patients need to be monitored. Another added advantage of taking reserpine could be a normal healthy life avoiding neurodegenerative diseases like Alzheimer disease.