International Journal of Advanced and Integrated Medical Sciences

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Comparative evaluation of metabolic adverse effects of mirtazapineversus paroxetine in patients with depression
  IJAIMS
ORIGINAL ARTICLE
Comparative evaluation of metabolic adverse effects of mirtazapineversus paroxetine in patients with depression
Shalini Chandra1, Kumar Mayank1, Rahul Ranjan1, Munish Kumar2, Iram Shaifali1, Rajib Karmakar1,Suruchi Prakash1
1Department of Pharmacology, Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh, India, 2Department ofPharmacology, Pt. Jawahar Lal Nehru Government Medical College and Hospital, Chamba, Himachal Pradesh, India
Corresponding Author:
Munish Kumar,Department of Pharmacology, Pt.Jawahar Lal Nehru GovernmentMedical College and Hospital,Chamba, Himachal Pradesh, India.
E-mail: pharmarohilkhand@gmail.com
Received: 02-04-2018
Accepted: 05-04-2018
Published: 16-06-2018
 
ABSTRACT
Background: Depression is the common psychological disorder worldwide andis a leading cause of disability. Second-generation antidepressants (mirtazapine[MIRT] and paroxetine [PAR]) are now acknowledged to be the first-line treatmentfor depression. The aim of the study was to comparatively evaluate MIRT andPAR with regard to metabolic adverse effects (body weight [BW], body massindex [BMI], fasting blood sugar [FBS], and lipid profile) in cases of depression.
Materials and methods: A prospective, randomized, open-label, and interventionalclinical study of 1 year duration was conducted at Rohilkhand Medical Collegeand Hospital, Bareilly. A total of 100 naive patients of depression of age group of18-65 years of both the sexes were randomly divided into two groups and wereadministered flexible-dose of MIRT 15-45 mg and PAR 12.5-37.5 mg daily.Patient's BW, BMI, FBS, and lipid profile were estimated at baseline and reassessedat 1 month, 3 months, 6 months, 9 months, and 12 months.
Results: MIRT groupshows statistically significant increase in BW (P < 0.0001), BMI (P < 0.0001), andFBS (P < 0.0001) after 12 months of therapy. Total cholesterol (TC), triglycerides(TG), and low-density lipoproteins (LDL) were also significantly raised (P < 0.05,P < 0.0001, and P < 0.0001, respectively). High-density lipoproteins (HDL) weredeclined significantly (P < 0.0001). However, none of the patients crossed thenormal range. Significant rise in BW (P < 0.0001) and BMI (P < 0.05) (althoughlesser than mirtazapine) and no statistically significant changes in FBS, TC, TG,HDL, and LDL values were observed in PAR group.
Conclusion: PAR was foundto be associated with lesser increase in BW and BMI as compared to MIRT in thetreatment of depression. Other metabolic parameters were not affected with PAR.However, mirtazapine had adverse impact on FBS, TC, TG, LDL, and HDL levels.The results of this comparative, prospective, randomized, open-label, interventional,and flexible-dose clinical study revealed that PAR was a safer and well-tolerated ascompared to MIRT in the long-term treatment of drug naive patients of depression.
KEY WORDS: Depression, metabolic parameters, mirtazapine, paroxetine
How to cite this article: Chandra S, Mayank K, Ranjan R,Kumar M, Shaifali I, Karmakar R,Prakash S. Comparative evaluationof metabolic adverse effects ofmirtazapine versus paroxetine inpatients with depression. Int J AdvInteg Med Sci 2018;3(2):22-29.
Source of Support: Nil
Conflicts of Interest: None
 
 

 

INTRODUCTION

Moreover, the depressive patient has feelings of guilt or lowself-esteem. Pharmacologic therapy is the foundation stone inmanaging depressive ailment. Antidepressants, at times referredto as happy pills, are psychotropic (mind-altering) drugsemployed to abate depression.[1] These drugs impinge on frameof mind, insight, awareness, and cognition. Antidepressantshave been classified based on differing modes of action of drugs,although the majority of drugs performed by acting on one ormore neurotransmitters at brain synapses. The scientific rationalefor their use is the serotonin (or monoamine or catecholamine)hypothesis of depression. Depression is due to a deficiency inone or other of three biogenic monoamines, namely, serotonin,norepinephrine, and/or dopamine.[2]

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The pharmacologic treatment strategies currently availableinclude tricyclic antidepressants (TCAs), selective serotoninreuptake inhibitors (SSRIs), serotonin-noradrenergic reuptakeinhibitors, and other atypical antidepressant drugs, such asmonoamine oxidase inhibitors. The choice of treatment formajor depressive disorder and its subtypes involves weighing therelative efficacy, side effect profile, and safety of treatment againstthe severity of illness as well as patient acceptance.[3] Newerclass of antidepressants (e.g., mirtazapine [MIRT], venlafaxine,and reboxetine) offers advantages over TCAs and SSRIs interms of superior safety indices. Compared with the SSRIs, theyprovide similar efficacy but different side effect profiles. Thedata pertaining to metabolic adverse effects of either MIRT orparoxetine (PAR) in patients of depression are not corroboratedin the Indian population subset.[4] Thus, this novel study wasplanned with the aim and objectives mentioned as:
  • To compare and evaluate the metabolic adverse effects ofMIRT and PAR with regard to body mass index (BMI), lipidprofile, and blood sugar levels in cases of depression
  • To observe whether there exists any gross advantage ofone drug over others in respect to metabolic adverse effectsprofile
  • To assess the long-term metabolic effects and safetyoutcomes of these antidepressants.

MATERIALS AND METHODS

This study was conducted as a prospective, randomized,interventional, open-label, and flexible-dose clinical study inpatients of depression receiving treatment with either MIRTor PAR at Rohilkhand Medical College and Hospital, Bareilly,Uttar Pradesh, India.

Approval from the Institutional Ethical Committee wasobtained, and the number is IEC/IRB No. IEC/66/2014. Eachsubject signed an informed consent form before participationand could withdraw without prejudice at any time. Registrationfrom Clinical Trial Registry India was also applied, and thereference number is REF/2016/09/012246.

Dose Schedule
  • Flexible doses of MIRT (15-45 mg/day) and PAR (12.5-37.5 mg/day) were administered as per the clinical response
  • No other antidepressant drug therapy was given to patients.

Inclusion Criteria

The following criteria were included in the study:
  • Patients of age group 18-65 years and of both genders
  • Newly diagnosed patients (drug-naive) of mild to moderatedepression falling under the group (F32) as per the criteriaof the 10th edition of the International Classification ofDiseases.

 
Exclusion Criteria

The following criteria were excluded from the study:
  • Patients with a history of taking antidepressants before thestudy
  • Patients with a history of diabetes mellitus, cardiovascular,hepatic, renal, and thyroid diseases
  • Dyslipidemic and obese patients
  • Pregnant and lactating females. Patients taking antiepileptics,antipsychotics, birth control pills, steroids, propranolol,thiazide diuretics, and agents that induce weight loss.

Sample Size
  • A total of 100 patients were included and each was allotteda reference number
  • Simple randomization was done. Odd numbers wereassigned to (MIRT = 50) and even numbers to group(PAR = 50)
  • Of these six patients dropped out of MIRT group (n = 44)during the study period, due to dizziness and somnolence,and five patients dropped out of PAR group (n = 45) due tosexual dysfunction and insomnia.

Data Collection Technique and Tools
  • A complete preliminary clinical examination was conductedon all the subjects included in the study to rule out any chronicailments referred to in the exclusion criteria. After initialscreening, the socio-demographic data regarding age, sex,socioeconomic status, family history, and other demographicparameters were recorded in the case report form. Patientswere then evaluated by senior consultant psychiatrist
  • For calculating BMI (kg/m2), patient's height and weight
  • were taken using measuring tape and weighing machine.Blood pressure was measured using standard protocol.Thereafter, relevant investigations were done. The patient'sfasting blood sugar (FBS) and lipid profile were estimatedat baseline
  • After baseline investigations, patients were randomlydivided into two groups. One group was administeredMIRT 15-45 mg daily, and the other group received PAR12.5-37.5 mg daily as per the clinical response.

Follow-up
  • Patients under study were subsequently monitored andreassessed at 1, 3, 6, 9, and 12 months
  • During each follow-up visit, the weight of the patient wasrecorded to calculate BMI, fasting blood glucose level, andlipid profile which was also estimated
  • Psychiatric evaluation of the patients was also done by theconsultant psychiatrist during each visit. All adverse eventsor associated side effects during treatment were recordedin the case report form. The treatment compliance wasevaluated at each monthly visit using tablet counts andquestioning the parents/relatives
  • Tolerability assessment: All adverse events during treatmentwere recorded in the case report form. Evaluation ofseverity of adverse drug effect was assessed using adversedrug reaction (ADR) severity assessment scale (modifiedHartwig and Siegel), which classifies ADR into mild,moderate, and severe.[5]

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Investigations Done During Follow-up
  • Blood sugar: FBS
  • Lipid profile: Low-density lipoprotein (LDL), high-densitylipoprotein (HDL), triglyceride (TG), and total cholesterol(TC).

Statistical Analysis of Data

Statistical analysis was performed using the software StatisticalPackage for the Social Sciences, windows version 21.Demographical data were compared by Chi-square test andcontinuous data such as change in body weight (BW), BMI,blood sugar level, and lipid profile (at baseline, 1, 3, 6, 9, and12 months) were compared using unpaired t-test and pairedt-test.

RESULTS

The two groups were found to be comparable with respect to age(2 = 0.8557, P = 0.3943) and sex (2 = 0.042, P = 0.8376).

Table 1 shows that there was a statistically significant increasein BW (up to 9.07 kg, P < 0.0001) in MIRT-treated group, andincrease was evident as early as after 1 month. About 73%subjects experienced weight gain more than 7%. There wasstatistically significant rise in FBS (up to 8.32 mg/dL, P < 0.0001)from baseline to end point. Alterations in FBS were observedas early as 3rd month and became statistically significant9 months onward. There was a statistically significant rise (up to11.89 mg/dL, P = 0.0037) in TC levels in MIRT group. The TGlevels also significantly amplified up to 6 mg/dL (P < 0.0001) atthe end point. As shown in Table 1, LDL levels were significantlyraised at the end point of study (P < 0.0001), whereas HDLlevels showed statistically significant (P < 0.0001) decrease at12 months in MIRT group.

Table 2 shows increase in BW (up to 4.33 kg, P < 0.0001) andBMI (up to 1.78 kg/m2), which was also found to be significantin PAR subjects, but increase was evident after 6 months. Only53% patients experienced more than 7% weight gain at theend point. There was no statistically significant rise in FBS inPAR-treated subjects (P < 0.6790, 12 months). No statisticallysignificant rise in either TC (P = 0.6455, at end point) or TG(P = 0.5551, at end point) parameters were observed in PARgroup. As also depicted from Table 1, both LDL and HDLparameters showed no statistically significantly alterations(P = 0.1264 and 0.165, respectively, at end point) in PAR treatedsubjects.

 
Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression

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Chandra et al. Adverse effects of mirtazapine and paroxetine

Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression

 
Graphs 1 and 2 compare BW and BMI between the two groups.

Graph 3 compares the alterations in FBS between MIRT - andPAR -related groups from baseline to 1, 3, 6, 9, and 12 months.Graphs 4 and 5 also show a comparative analysis of TC andTG between both the groups. A comparison of LDL andHDL levels between two groups is also observed in Graphs 6and 7, respectively. Table 3 shows the adverse effects seen inboth groups. Almost all the adverse effects were mild accordingto Hartwig Severity Assessment Scale.

DISCUSSION

The drugs under investigation in this study, MIRT and PAR, in longtermcomparative evaluation have confirmed nearly comparableefficacy[6,7] but fewer long-term data are existing pertaining to theirmetabolic adverse effects particularly in Indian population.[8]

The two groups in the present study were matched for propercomparative evaluation. All the patients who were enrolled forthe purpose of the study were having first depressive episodeand had never received antidepressant drugs for any purpose.The groups were also in line with regard to mean age, gender,locality, educational, and socioeconomic status. Their baselinemetabolic parameter values with respect to BW, BMI, FBS,and lipid profile were also noted to be statistically comparablebetween MIRT - and PAR -treated groups.

Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression
Graph 1: Comparison of mean weight in Groups I and II in follow-up visit

Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression
Graph 2: Comparison of body mass index in Groups I and II infollow-up visit

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Chandra et al. Adverse effects of mirtazapine and paroxetine

Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression
Graph 3: Comparison of mean fasting blood sugar in Groups I andII in follow-up visit

Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression
Graph 4: Mean total cholesterol in Groups I and II in follow-upvisit

Flexible dose schedule of both drugs was used, PAR 12.5-37.5 mg/day and MIRT 15-45 mg/day depending on theevaluation of clinical condition and clinical response by theconsultant psychiatrist, though initially lower doses wereadministered. Various studies have used similar dosage rangeswith MIRT[7,8] and PAR.[9,10]

Despite adequate control with the therapy, dropouts within theMIRT - and PAR-treated groups were six and five subjects,respectively. The primary reason for dropouts was adverse effectsobserved in two groups. Four subjects from MIRT discontinueddue to weight gain and two subjects due to somnolence. FromPAR group, three subjects due to sexual dysfunction and twosubjects because of insomnia discontinued the treatment. Weightgain is a relatively common problem during both short-term andlong-term treatment with antidepressants, and it is an importantcontributing factor to noncompliance.[11] Similar dropouts werealso reported by various other studies.[12,13] Sexual dysfunctionand gastrointestinal symptoms such as nausea and vomiting werefound to be reasons for discontinuation with PAR as observedwith other studies also.[14,15]

 
Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression
Graph 5: Mean triglycerides in Groups I and II in follow-up visit

Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression
Graph 6: Mean low-density lipoprotein in Groups I and II in follow-up visit

Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression
Graph 7: Mean high-density lipoproteins in Groups I and II in follow-up visit

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Comparative evaluation of metabolic adverse effects of mirtazapine versus paroxetine in patients with depression


In this study, MIRT caused a significant rise in weight as earlyas after 1 month of the therapy and mean total weight gain of9.07 kg was found at the end point (12th month), whereas thereis lesser increase in weight of approximately 4.33 kg in the PARtreatedgroup at the end point. There are plentiful researcheswhich had confirmed that MIRT was responsible for rapid gain inweight.[16,17] Surprisingly, in one placebo control, double-blind trialpatients receiving MIRT gained only 1.4 kg weight over 1 year ofcontinuation therapy, which did not support our findings.[18]

With regard to PAR, there are diverse results concerningweight gain.[19] A number of studies reported weight gain;[20-22]nevertheless, many noted loss of weight.[23]

One study also concluded that both PAR and MIRT may causeweight gain, but mean weight change among MIRT group washigher than among PAR group.[24]

The probable reason for MIRT-induced weight gain is a disorderof the neurobiological controls that adjust food intake and alsochanges in leptin and the tumor necrosis factor-alpha cytokinesystem.[25,26]

 
In our study regarding FBS, it was observed that MIRTaltered blood sugar levels significantly from the 9th monthonward till the end point at 12th month (P < 0.0001), withapproximately 7.32 mg/dL rise in blood sugar level. However,PAR seemed to have no impact on FBS values. There isnumber of researches which confirmed our findings.[7,27] Ourfindings are partially in contrast to that of study of Laimer etal.[26] who found no effect on MIRT on FBS values despitegain in weight. Improved glucose tolerance during treatmentwith MIRT may, at least in part, be mediated by a reductionof cortisol secretion, because cortisol plasma levels arereported to be elevated in depressed patients and it was foundthat they can be lowered by antidepressant treatment withMIRT. In our study, PAR had no influence on FBS parameter.However, in literatures, PAR has diverse effect on FBSvalues. In one study, PAR was associated with an increasedlevel in FBS.[10] Conversely, FBS values improved in anotherstudy.[19] A statistically significant increase in TC (P < 0.05)was observed in subjects of MIRT group. TG and LDL levelswere also significantly raised (P < 0.0001 and P < 0.0001,respectively). MIRT also significantly lowered (P = 0.0001)serum HDL levels at the end point of the study. Various otherstudies also confirmed that MIRT is a drug that is known tocause dyslipidemia.[7,27] PAR group, however, did not showany alterations in TC, TG, LDL, and HDL levels. Conversely,few studies revealed that treatment with PAR was associatedwith a significant increase in levels of TC, HDL, and LDLlevels.[28,29] Increased appetite, carbohydrate craving, reducedinsulin sensitivity, and abnormalities in lipid metabolism, andhyperprolactinemia are believed to be the mechanisms behindthe development of these metabolic effects.[7] Hence, it issuggested that patients on MIRT or SSRIs should carefullybe monitored for obesity and dyslipidemia as diverse resultswere obtained with respect to metabolic considerations. Ourstudy findings nonetheless revealed that when these two drugswere compared for their effects on serum lipids MIRT disturbslipid profile more unfavorably than PAR.

The adverse effect profile is an important consideration whileprescribing the drug in the treatment of depression. Besidescomparing metabolic parameters, the present study alsocompared various other adverse events over 12 months oftreatment with MIRT and PAR. The most common adverseexperiences with MIRT were increased appetite (75%),followed by somnolence (57%), fatigue (27%), dizziness (18%),constipation (18%), headache (18%), nausea (16%), dry mouth(9%), anxiety (7%), and tremors (2%). With PAR treatmentother common adverse events were increased appetite (56%),which were followed by nausea (49%), insomnia (44%), sexualdysfunction (22%), anxiety (22%), tremors (18%), constipation(9%), dry mouth (7%), dizziness (7%), and least experiencedwas somnolence (4%). In line with our findings, few studiesnoted that anticholinergic events and other events, includingtremors and dyspepsia were less common and increased appetite,somnolence, headache, fatigue, constipation, and dizziness weremore common with MIRT.[8,30,31]

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This is probably as a consequence of the drug's higher affinityfor central histaminergic one receptor.[8] Consistent to ourfindings, few studies also reported that MIRT had no sexual sideeffects in contrast to SSRIs and less incidences of tremor andnausea.[6,31] As observed in the present study, sexual dysfunctionand more gastrointestinal side effects such as nausea, vomiting,dry mouth, constipation, and headache with PAR treatment werealso reported in few studies.[8-10,15,32]

However, in our study, almost all the adverse effects were mild,and no adverse effects which required hospitalization were foundwith either drug. Modified Hartwig and Siegel Assessment Scalewas deployed to assess severity of adverse drug effect, whichclassifies ADR into mild, moderate, and severe.

CONCLUSION

This study reinforces the need to monitor depressed patientsregularly for weight gain, glucose dysregulation, and lipidabnormalities. Baseline monitoring of weight, blood sugar,and lipid profile is necessary before initiating treatment withantidepressants.

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