Selective Serotonin Reuptake Inhibitors and Nutraceutical Combination in Major Depression Disorder: A Case-Control Study

Abstract

Introduction:

Major depressive disorder (MDD) is a primary cause of disability in adults, affecting daily functioning and decreasing quality of life. The focus on the role of nutraceuticals as adjunctive treatments to improve antidepressant response is paying growing interest. The study aims to compare the antidepressants response in the utilization of selective serotonin reuptake inhibitors (SSRIs) versus a combination of SSRIs and nutraceutical supplements based on S-Adenosyl methionine (SAMe), N-acetylcysteine (NAC) and folate in terms of efficacy and tolerability.

Methods:

A case-control study was carried out between March 2018 and September 2019. Cases and controls were evaluated through the following scales: Hospital Anxiety Depression Scale (HADS); Clinical Global Impression (CGI); Patient Global Impression of Improvement (PGI-I); Antidepressant Adverse Events checklist (AES).

Results:

A significant difference between the two groups of patients emerged at T₁ in the HADS-A (p = 0.004) score and in the CGI score (p = 0.01), due to a major improvement in patients with a nutraceutical co-prescription. At T₃ a significant statistical difference emerged, showing a greater improvement at HADS-D in the case group (p = 0.006), confirmed by a higher remission rate in patients taking a nutraceutical co-prescription. No differences in terms of adverse events emerged.

Conclusion:

This study shows promising data about the role of nutraceuticals as adjunctive treatment in major depressive disorder to improve SSRIs efficacy, with good tolerability. More data are needed to confirm these results, particularly about the role of nutraceuticals to decrease the latency of SSRIs response.

Introduction

Major depressive disorder (MDD) is a primary cause of disability in adults, affecting daily functioning, increasing the risk of suicidal behavior, and decreasing quality of life.^1,2 Depressive disorders have a lifetime prevalence of 6–21% and are one of the highest causes of morbidity in the world. Considering the impact of depression on public health, effective treatments of this disorder are an important objective to reach.³ The monoaminergic theory of depression postulates that deficient monoamine (serotonin, norepinephrine, and/or dopamine) concentrations in the brain contribute to the etiology of depression.⁴ Selective serotonin reuptake inhibitors (SSRIs), which selectively block serotonin reuptake via the serotonin transporter, have been a pharmacological mainstay in the treatment of major depressive disorder for over 25 years. Despite this, there are still many problems related to this treatment: the high rate of non-compliance or incomplete remission of symptomatology, the variable tolerability and, given the latency of clinical response that frequently appear much later than the onset of adverse events, the high number of dropouts.⁵ In this context, the focus on the role of nutraceuticals as safe and effective adjunctive treatments to improve therapeutic response to SSRIs is object of growing interest. Behind this attention there are evidences dealing with the action of these substances on brain pathways associated with depression.^6,7

In particular, S-Adenosyl methionine (SAMe) is a nutraceutical naturally present in the body and is an active cofactor in the single carbon cycle and involved in the synthesis of monoamines, in particular serotonin, noradrenaline and dopamine.⁸ Another important nutraceutical is N-acetylcysteine (NAC), a derivative of the amino acid cysteine that has collected multiple evidences in the management of neurological and psychiatric diseases. Its effect in depression is mainly related to its antioxidant properties and to its ability to increase glutathione levels in the central nervous system. The co-prescription of nutrient-based “nutraceutics” could be a potential new approach to increase a particular neurobiological activity of an antidepressant drug or to reduce response time.

This study aims to compare the antidepressant response in the utilization of SSRIs versus a combination of SSRIs and nutraceutical supplement based on S-Adenosyl methionine (SAMe), N-acetylcysteine (NAC) and folate in a sample of patients suffering from major depressive disorder.

Specifically, the primary objective consists in the comparison of the two groups in terms of efficacy over time comparing the scales’ scores; the two groups have been compared also in terms of HADS response rate after 8 weeks. The secondary objective is the comparison of the two groups in terms of tolerability.

Materials and Methods

A case-control study was carried out between March 2018 and September 2019. Data concerning patients from Anxiety and Depression Clinic of the Psychiatric Unit of Varese (Azienda Socio-Sanitaria Territoriale “ASST” Sette Laghi) were collected. Data referring to cases and controls included diagnosis of MDD from moderate to mild severity (according to DSM-5 criteria). Patients whose clinicians prescribed SSRIs with nutraceutical supplementation were included in the case group, while patients receiving a prescription of SSRIs were included in the control group. Nutraceutical supplementation evaluated in this study was the prescription of SAMe, NAC and folate combined in a single formulation named Triadenor, at the dose of two tablets per day for the first 8 days and one tablet per day for other 8 weeks, as clinicians used to do in their clinical practice. Each tablet includes NAC 200 mg, SAMe 200 mg and folate 200 μg. To be enrolled patients had to fulfill the following inclusion criteria: age ≥ 18 years at the time of the first visit, affected by MDD, from mild to moderate severity, drug-naive or without a psychopharmacological treatment for at least 6 months, agree and able to sign an informed consent for the study participation and for the use of data in an anonymous form. Conversely, we considered as exclusion criteria a current diagnosis of major psychiatric disorders and/or to be enrolled in other on-going studies. The following validated questionnaires were administered to the patients to assess psychopathological symptoms:

– Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depressive symptoms. This scale is a widely used screening instrument with seven anxiety and seven depression items. The scores of the anxiety and depression subscales range from 0 to 21. A total score ≥ 8 has been used to establish the absence of symptoms for both anxiety and depression;^9,10

– Clinical Global Impression (CGI) was used to evaluate the global severity of patients and to assess the global improvement and the efficacy of drugs related to their side effects;^11,12,13

– Patient Global Impression of Improvement (PGI-I) was used to assess the patients’ perception of symptoms, it is a global index to rate the impression of patients dealing with the response to a therapy;¹⁴

– Antidepressant Side-Effect Checklist (ASEC) to evaluate the treatments emergent adverse events (TEAEs).^15,16

HADS was administered to all patients at first visit at baseline, after one week (T₁), after 4 weeks (T₂) and after eight weeks (T₃). PGI-I, CGI and ASEC were administered at T₁, T₂ and T₃. Since that the patients were given the questionnaire (HADS and PGI) or assessed through the questionnaires (CGI and ASEC) without knowing their allocation, the assessment was considered blind.

The sample size was estimated based on previous studies on similar comparisons.^17,18 Statistical analysis was performed using SPSS Inc. (released software 2015, IBM SPSS statistics for Mac). D’Agostino & Pearson tests were used to evaluate the normal distribution; Fisher exact test or Chi-square test were used to compare dichotomous variables, depending on the number of events, such as response rate at 8 weeks and the number of patients presenting TEAEs; T-Student test was used for continuous variables, such has the evaluation of the scales’ scores during time. Statistical significance has been established for a p-value <0.05 (two-tailed).

This study observed regulatory and legal requirements (DL n.211, 24 June 2003, and DM 17 December 2004), according to the Declaration of Helsinki’s ethical principles. Following the Institutional Review Board approval, all patients were specifically informed about the opportunity to participate in this study and signed a written specific consent before the enrolment. The design, analysis, interpretation of data, drafting, and revisions followed the strengthening reporting of observational studies in epidemiology (STROBE) statement. The study was non-advertised, and no remuneration was offered to encourage patients to give their consent for data collection and/or analysis of their data.

Results

Sociodemographic and Clinical Characteristics of the Sample

Data from 64 patients were recruited. From this sample 32 patients fulfill the criteria to be included in the case group and 28 in the control group. The mean age at the first visit was 44.84 (SD 9.73) years for the cases and 46.48 (SD 3.6) for the control group. In the case group 52% of patients were males, 44% in the control group.

Dealing with the clinical characteristics, no statistical differences between the two groups emerged at the baseline, as shown in Table 1. Depressive and anxious symptoms were tested through the HADS questionnaire. At baseline the median (range) score was 14.26 (4.23) for the case group and 13.7 (3.79) for the control group at the HADS-D (hospital anxiety and depression scale-depression items) (p = 0.23 at unpaired t-test); the mean scores of the HADS-A (hospital anxiety and depression scale-anxiety items) were 17.48 (SD 5.79) in the case group and 18.43 (SD 5.59) in the control group without statistically significant differences between the two samples (p = 0.44 at unpaired t-test).

Table 1. Baseline Sociodemographic and Clinical Characteristics of the Sample.

BASELINE		Case group N = 32		Control group N = 28		Test of significance
Age Mean (DS)		44.84 (9.73)		46.48 (SD 3.6)		0.89
Gender % (N) Male Female		52% (17) 48% (15)		44% (12) 56% (16)		0.45
Education % (N) Junior High School High School Bachelor’s degree		-- 59% (19) 41% (13)		-- 53% (15) 47% (13)		0.63
Occupational Status % (N) Employed Unemployed Retired		78% (25) 6% (2) 16% (5)		86% (24) 4% (1) 10% (3)		0.23
Marital Status % (N) Unmarried Married Widowed		41% (13) 56% (18) 3% (1)		50%, (14) 50%, (14)		0.8
Comorbidities % (N) Yes No		25% (8) 75% (24)		21% (6) 79% (22)		0.77
Psychotherapy % (N)		6% (2)		4% (1)		1
HADS Depression: Mean (SD) Anxiety: Mean (SD)		14.26 (4.23) 17.48 (5.79)		13.7 (3.79) 18.43 (4.59)		0.23 0.44

Abbreviations: N = number; SD= Standard Deviation.

Primary Results: Efficacy

As shown in Table 2, dealing with HADS a significant statistical difference emerged at T₁ and T₃; in both cases the difference was due to a greater improvement in the case group. To note that at T₁ the difference was due to anxiety items (p = 0.004), while at T₃ to the depression items (p = 0.006).

Table 2. Scales Scores Comparison Between the Two Groups Over Time.

		Case group Score (SD)		Control group Score (SD)		p
HADS-D Time1 HADS-A Time1		13.24 (4.36) 14.56 (5.27)		11.41 (4.74) 19.71 (3.13)		0.74 0.004
HADS-D Time2 HADS-A Time2		13.06 (7.07) 12.33 (4.56)		16.29 (5.73) 14.98 (6.23)		0.59 0.42
HADS-D Time3 HADS-A Time3		9.31 (7.09) 8.23 (6.46)		14.50 (7.20) 9.21 (5.4)		0.006 0.74
CGI Time1		5.69 (3.79)		7.85 (4.29)		0.01
CGI Time2		4.36 (3.77)		6.72 (3.89)		0.06
CGI Time3		3.25 (3.55)		5.36 (3.77)		0.10
PGI-I Time1		3.76 (1.58)		3.69 (1.85)		0.89
PGI-I Time2		7.31 (1.71)		7.50 (1.50)		0.62
PGI-I Time3		3.68 (1.97)		3.57 (1.34)		0.85

Abbreviations: HADS-D = Hospital Anxiety and Depression Scale-Depression items; HADS-A = Hospital Anxiety and Depression Scale-Anxiety items; SD = Standard Deviation; N = number.

Regarding CGI only at T₁ a statistically significant difference emerged, due to a greater improvement in case group. PGI-I did not show any difference during time.

Comparing the percentage of patients achieving an HADS score remission rate (HADS subscales’ scores ≥ 8) at T₃, a statistically significant difference emerged (p = 0.003) due to a greater improvement in the case group at HADS-D (as shown in Table 3).

Table 3. HADS Remission Rate at Time3.

		Remission Rate		p
HADS-D Case group % (N)		50% (16)		0.003
HADS-D Control group % (N)		22% (6)
HADS-A Case group % (N)		48% (16)		0.43
HADS-A Control group % (N)		36% (10)

Abbreviations: HADS-D = HADS-Depression items; HADS-A = HADS-Anxiety items.

Secondary Results: Tolerability

The number of patients presenting TEAEs at the ASEC was compared through Fisher Exact Test at T₁, T₂ and T₃. No statistical significant differences emerged between the two groups. The most frequent TEAE was sickness, followed by headache at T₁; at T₂ headache was the most frequent TEAE reported by patients, while at T₃ sexual problems were reported by one patient in the case group and weight gain by one patient in the control group.

Discussion

This study shows a statistically significant difference at T₁ CGI and HADS-A scores (respectively p = 0.01 and p = 0.004), and a statistically significant difference at T₃ HADS-D score (p = 0.006). At T₃ also the HADS-D remission rate was significantly higher in the control group (p = 0.003). Dealing with TEAEs no differences emerged comparing the two groups.

The faster improvement of the cases taking an additional therapy with nutraceuticals in the HADS score was related to the anxiety items. This could be due to the nutraceuticals role of decreasing anxiety levels associated to SSRIs prescription. This result has been confirmed also by other authors highlighting the role of nutraceutical co-prescription in decreasing the level of anxiety of the first period of SSRIs therapy.¹⁹ This factor could be useful also in reducing the therapies discontinuation.²⁰ It has long been postulated that the dysregulation of neurotransmitters may be a cause of anxiety. These neurotransmitters include GABA, serotonin, dopamine and norepinephrine.^21,22 Amino acids such as N-acetyl-cysteine, L-tyrosine, L-tryptophan and methionine are known precursors for specific neurotransmitters and are used to ameliorate stress and anxiety symptoms.²³ In spite of this, there are few data supporting the nutraceutical co-prescription to specifically reduce the latency of SSRIs, but there are more evidence dealing with their role into the mood improvement. Sarris and co-authors underlined the role of SAME into the catecholamines methylation and to increase serotonin turnover, reuptake inhibition of norepinephrine, enhanced dopaminergic activity, decreased prolactin secretion, and increased phosphatidylcholine conversion.⁶ Folate, present in the formulation prescribed in the study in high quantity (200 μg per tablet), appears to play a crucial role to improve depressed mood; its beneficial role in patients with depressive symptoms seems to be related to serotonin. Also Bender and coauthors²⁴ confirmed the implication of folate into mood regulation, underling in a review with meta-analysis including 43 studies, a significant, small effect size, such that individuals with depression had lower folate levels than those without depression. Folate deficiency seems to be associated with low levels of the serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid.²⁵

Another possible explanation for the antidepressant efficacy of these compounds may reside with their anti-inflammatory properties, which are well demonstrated with SAMe and omega-3.¹⁹ NAC treatment is also associated with a diminished oxidative stress reflected in preserved antioxidant levels, lower inflammation mirrored in lower interleukin levels and less vasopressor requirement.

Due to these evidences the International Society for Nutritional Psychiatry Research has issued a consensus statement that “nutrition and nutraceuticals should now be considered as mainstream elements of psychiatric practice, with research, education, policy and health promotion reflecting this new paradigm”.²⁵

Conclusion

Nutraceuticals could be used in major depression disorder as adjunctive therapies with antidepressant to shorten response time and to improve antidepressant efficacy. They could represent a useful, safe and effective tool especially in those patients with comorbidities and polypharmacotherapies.

Despite some limitations, such as the not randomized study design and the moderate sample size, this study shows promising data about the role of nutraceuticals as adjunctive treatment in major depressive disorder to improve SSRI efficacy, with good tolerability. More data are needed to confirm our results, particularly about the role of nutraceuticals to decrease the latency of SSRI response.

Table 4. Treatment Emergent Adverse Events During Time.

		Case group %, (N)		Control group %, (N)		p
Time1		6% (2)		3% (1)		1.00
Time2		12% (4)		7% (2)		0.98
Time3		3% (1)		3% (1)		1.00

Abbreviation: N = number