INTRODUCTION:

Major depressive disorder (MDD) is a principal cause for loss of Disability Adjusted Life Years (WHO). [1] Literature search finds MDD with significant morbidity and mortality. [2] Literature evidence in Kessler et al. study shows the USA 2001 survey on National Comorbidity, showed overall lifetime prevalence for MDD was16.2%. Major Depressive Disorder (MDD) is the most prevalent of all psychiatric disorders. [3] Previous studies evidenced MDD affecting approximately 322 million people worldwide. [4] Literature shows in the United States, nearly 225 million people, with depression irregular to their work have caused an annual loss of $36.6 billion US dollars. [5] This review analyzes MDD cause significant morbidity and mortality in adults as well as children. [6, 7] Previous literature has revealed approximately 13 years later; depression is predicted to be a leading cause of disability in the United States. [9] Indeed, depression disables the person, adversely impact the quality of life medical comorbidity and mortality. [9, 10] In depression, antidepressants are the treatment of choice. Perhaps, in the cases of mild depression, psychotherapy is also a treatment of choice. The combination of antidepressants with cognitive behavioral therapy is the best mode of treatment for depression. [11] Although; relapse, less remission, and high dropouts are common in these interventions. [12, 13, 14]

Risk of relapse in major depression disorder

MDD has a high risk of relapse evidenced in the previous literature up to 85% after one MDD episode. [15] Additionally, evidence reveals the presence of residual symptoms after recovery and many previous episodes of depression are predictors of the increased number of relapse. [16, 17, 18] Shreds of evidence showed antidepressants leading improvement in the patient, low clinical remission in patients shows a high risk for relapse.[19] Pieces of evidence confirm adjunct therapies enhance the beneficial effects of antidepressant treatments. [20] Pieces of evidence reveal antidepressant treatment with various classes of antidepressants treats patients MDD in their acute phase; additionally, it reduces the risk of relapse of depressive episodes among patients. [21, 22] Therefore, patients’ need to be educated on adherence to antidepressant treatment; its significance in maintaining remission and reducing treatment complains. Previous literature shows the estimate that only 10% of patients with MDD are receiving adequate dosage and duration with antidepressants. [14] There are various pharmacological agents are used for the treatment of MDD, commonly selective serotonin reuptake inhibitors (SSRIs) used as first-line treatment for MDD for adults and children, [ 6, 7, 23] Various SSRIs are used for maintenance therapy to prevent relapse. [19, 20]

List of drug agents used in Major Depression Disorder

MDD drug agents

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin norepinephrine reuptake inhibitors (SNRIs)

Norepinephrine- dopamine reuptake inhibitors (NDRIs)

Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs)

Analysis of literature reviews evidence other than selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), norepinephrine- dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) is the common drug agents used in Major Depression Disorder. [20, 21] Shreds of evidence shown that cognitive behavior therapy (CBT), with or without pharmacotherapy, is beneficial in reducing the risk of relapse of depressive episode in MDD patients. [18] Regarding relapse risk in MDD pieces of evidence show, partially remitted patients had higher relapse rates. [22] Correlation between partially remitted patients having relapse risk in MDD is strong; indeed, the residual symptoms in these patients could be used as an indicator to predict relapse. [22, 23] Hence the current study views that goal set in MDD treatment should be after the full remission that can pave up lowered the risk for relapse. Even though some studies have shown the efficacy of SSRI in MDD relapse prevention, there are limited comprehensive review studies comparing SSRIs with other clinical modalities. Indeed, there are no clear-cut views regarding various antidepressant, and CBT treatment preventing MDD relapse. Different antidepressant classes may differ from their efficacy. The current review study aims to compare the studies focused on SSRIs with other interventions in preventing relapse in MDD. The current review study provides clinicians additional information as a guide for best treatment modalities and maintenance therapy for the major depressive disorder.

METHODOLOGY:

Search strategy: This literature review was completed using electronic databases, Ovid Medline, and PsycINFO from dating back to 1987 to August 2018 since US Food and Drug Administration approval of the first SSRI to the present. The keywords used for the search were, depress, depression, major depression, major depressive disorder, prevention of MDD, prophylaxis, relapse, SSRI/specific serotonin reuptake inhibitor, antidepressants, and cognitive behavioral therapy. This strategy identified 240 relevant articles.

Inclusion and exclusion criteria

Three authors independently reviewed the abstracts of the 240 articles and selected that met the following study selection inclusion criteria:

(1) The articles published in language English.

(2) The articles published other than the English language with English translation available

(3) The articles published in a peer-reviewed journal

(4) The articles focused on SSRI and CBT used for MDD relapse

(5) The articles on treatment for MDD and reducing relapse.

6) The articles that do not meet the above criteria are excluded.

The search results in 25 studies selected based on screening abstracts fit into inclusion criteria. Further, the full article text reviewed to confirm the articles meet the inclusion criteria. The reviewers reached consensus on 20 selected studies to include in the review. Figure 1 depicts the flowchart of the procedure adapted article selection. Extracted data of this review research are the key findings, which bases on the full texts and tables of the selected research articles. Table 1 shows the findings of the selected articles included in this review.

Figure 1: Flowchart depicting refining procedure of article selection

RESULTS:

Maintenance of major depressive disorder using selective serotonin reuptake inhibitors

The results of the study depicted in Table 1. Shreds of evidence indicate relapse risk in MDD, among which the ten studies specified relapse rate or risk ratios among SSRIs. Commonly SSRIs are first-line agents for initial treatment and prevention of MDD. The able treatment of the depressive episode and prevention future episodes is important Sertraline 50–200 mg/day evidenced the relapse rate of 8.5 percent in patients who underwent maintenance therapy for 44 weeks.[23] Studies evidenced in depressed children and adolescent’s fluoxetine significantly lower in an RCT [34%] in 36-weeks of follow up. [27] SSRIs compared in a naturalistic long-term study current study compared four of them against the relapse rate of MDD. This results supported by other meta-analyses of escitalopram, sertraline, citalopram, and paroxetine, that evidenced significant decreases in relapse rates. The studies compared the drug with placebo to find the relapse rate.

Pieces of literature evidenced Escitalopram is a prophylactic agent against depressive episodes, its efficacy of showed 36% better than that of other drugs, fluoxetine which showed 33.3% sertraline (21.3%) and paroxetine 12.85%. However, values among SSRIs as a prophylactic agent differ, one of the literature study evidenced, no significant difference assessed on Montgomery Asberg Depression Rating Scale (MADRS). [18] In realistic views, it appears the continuation of SSRIs has a better probability of maintaining remission within the first year. One of the literature studies has proven, comparing data on discontinuation of SSRIs 0.70% with the continuation of SSRIs 0.40% in maintaining remission. Other evidential study demonstrated reduced remissions 8.5% against 19.5% placebo in a 44-week maintenance trial [24] further 13% against 45.7% placebo in a 16-week maintenance trial. [25] Additionally, a randomized clinical trial of 24-week maintenance studies have evidenced, comparing sertraline with another SSRI, showed sertraline having a lower relapse rate of 2% against 9% with paroxetine with the dosage of 20–40 mg daily. [26] The evidence has demonstrated, the relapse rate of paroxetine was directly comparing with Hypericum extract 160-week maintenance therapy, indicated both SSRIs were equally as effective at preventing relapse from an episode of moderate to severe depression. [12] Analyzing the results experimental data on a study by Yang and colleagues indicates adult MDD patients on fluoxetine had a lower relapse rate that of 45.9% than the placebo group 72% after a 1-year follow up. [23] The current analyze in depressed children, and adolescents the relapse rate with fluoxetine is lower in RCT, at 34% against 60% placebo on 36-week follow up. [27] Literature also depicted the results of meta-analyses on escitalopram, sertraline, citalopram, and paroxetine, showed statistically significant decreases in MDD relapse rates compared with placebo. [19, 20]

The search engine of current study recognized there are limited studies comparing SSRIs for preventing depressive episodes. Four pieces of evidence that found with SSRIs compared in a naturalistic long-term study. The results of these studies demonstrated escitalopram having high efficacy in preventing depressive episodes efficacy of 36%, followed by fluoxetine 33.3%, sertraline 21.3%, and paroxetine 12.85%. However, these exceedingly differing values showed no significance on the Montgomery - Asberg Depression Rating Scale (MADRS). [18]

In one of the naturalistic study, the continuation of SSRIs significantly found to be efficient in maintaining remission, i.e., 0.70 within the first year compared with discontinuation of SSRIs, i.e.’0.40). [6] However, when choosing SSRIs’ as first-line treatment for the major depressive disorder, this study suggests on the ground of large-scale clinical trial evidence using SSRIs with another treatment choice such as SNRIs, TCAs, atypical antidepressants, and CBT is defensible. Other related evidence observed in one clinical trial, a 6-month maintenance phase of treatment with fluvoxamine, 8.9% of patients relapsed within the first two months follow-up. However, in this study relapse rate for placebo, was not reported; thus not able to assess significance. [13]

In the current study, the search engine spotted literature on comparing selective serotonin reuptake inhibitors (SSRIs) against serotonin-norepinephrine reuptake inhibitors (SNRIs) for major depressive disorder. In one such literature study, Bauer et al., compared venlafaxine with SSRIs; [6] other 28 similar studies are compiled for the meta-analysis to establish the efficacy of venlafaxine compared with SSRIs. Analysis of review indicated Venlafaxine produce favorable outcomes than that of imipramine, clomipramine, and amitriptyline, thiepin, amineptine and maprotiline with an odds ratio of 1.22, which showed 95% confidence interval (CI) 0.96–1.54. One of the studies revealed that the effectiveness of venlafaxine in reducing relapse after a major depressive episode, i.e., OR = 0.37, CI 0.27–0.51), compared with placebo. However, the relapse rates for SSRIs yet not calculated. Also, the relapse rates not compared between SSRI and SNRIs. Other literature studies on other SNRIs such as duloxetine found that SSRI use produced a more significant decrease in the MADRS total score. [20] One of the reviewed studies by Garnock-Jones et al. indicated escitalopram is faster short-term response than venlafaxine, thus escitalopram preferred drug in the cases of acute and severe MDD. [20] Literature studies on dropout rates in collective studies did not show the notable difference between venlafaxine against SSRI treatment, i.e., 95% CI 0.95–1.19; p = 0.26, however, showing the observed incidence of side effects in the venlafaxine is higher by a statistically relevant shown OR of 1.45 (95% CI 1.23–1.70; p < 0.001). [27] Regarding venlafaxine commonly seen side effects include dry mouth, insomnia, nausea, and vomiting, additionally, evidenced increased suicide risk. [7, 20] indeed low OR for suicidal risk and suicidal thoughts are seen in SSRIs than that of venlafaxine. [32] Review study has analyzed that despite the side effect outlined and patient preference data evidence venlafaxine favorable choice for relapse prevention.

Selective serotonin reuptake inhibitors and tricyclic antidepressants in maintenance therapy

The current study had reviewed literature that compares selective serotonin reuptake inhibitors and tricyclic antidepressants in maintenance therapy of MDD. Review analysis has indicated lesser relapse rates with TCAs in the treatment of MDD. One of the studies has proven to reduce the relapse rate, directly comparing the relapse risk between TCAs against SSRIs. In a meta-analysis of 30 RCTs on 4890 patients indicated the reduction of relapse risk for TCAs, with OR, = 0.29 that is Cl 0.23–0.38 at 1-year follow up. Pieces of evidence show the OR was similar for SSRIs. Shreds of evidence indicate that though the OR was superior to TCAs than for SSRIs, although no statistical significance indicating relapse risk. further, observing the literature studies, CI was superior to TCAs, shows the heterogeneity of the RCTs. [19] The review analysis observes pragmatic open-label trial study conducted for all antidepressants; such as fluoxetine, mirtazapine, mianserin, amitriptyline, and tianeptine with the full versus partial remitters. Continued treatment showed at week 52; the relapse rate was 8.33% for full remitters and higher for partial remitters, i.e., 25%. The study lacks the analysis according to antidepressant type. [22] The studies by Fava et al., antidepressants or antidepressants with CBT has showed reduced relapses with antidepressants with CBT than antidepressants alone in the treatment of MDD. Though the review analysis carried on the antidepressants of various drug classes, approximately 50% of them are TCAs. The relapse rate evidenced lower after combining two to four years follow up. [29, 30]

Psychotherapy and alternatives Treatments for MDD

There are various other alternatives treatments for selective serotonin reuptake inhibitors for maintenance therapy for major depressive disorder. Evidence shows that cognitive therapy, behavioral therapy, and cognitive behavioral therapy empirical support for effectiveness in the treatment of depression. Cognitive behavior therapy is adjuvant to selective serotonin reuptake inhibitors for maintenance of major depressive disorder, CBT is a desirable non-pharmacological therapeutic option used in addition to or in place of SSRI. Many patients on therapy are wary of pharmacotherapy when treating the acute phase of MDD as well as maintenance phases. One of the previous literatures on naturalistic prospective study for 34 months by Peselow and colleagues analyzed the utility of CBT as an adjunct therapy to SSRI. Evidence showed alternative to typical antidepressants Hypericum extract has minimal side effects. The dose of 3× 300 mg daily is not shown the relapse rate with significant differing to paroxetine dose 20 or 40 mg/day. Evidence also revealed between Hypericum extract and paroxetine no significant differences in the relapse rate. Patients in treatment with the SSRI group for MDD, the duration between depressive episode and relapse was longer; also the remission maintenance rate was higher with the SSRI + CBT, 41 percent. On the other hand, 18 percent of patients in treatment only with the SSRI group maintained remission. [18] The previous study by Fava et al. evidenced the maintenance therapy at two years follow up groups using pharmacotherapy alone, and CBT with pharmacotherapy showed no significant difference [29]. Nevertheless, patient with extended the follow-ups for four to six years, the long-term benefits of CBT clearer with fewer relapses (35%) and the relapses using placebos is70%. Past literature evidence shows CBT benefits on adolescents and children not as effective as pharmacotherapy; particularly MDD with comorbid diagnoses. Indeed, cognitive development in children, not complete CBT is not adequate as an impartial therapy in pediatric MDD. [7]

DISCUSSION:

In the mental health profession choosing antidepressant medicine is based on patients symptoms, the presence of other medical conditions medicines patient already taking, cost of treatments with patients affordability, and potential side effects. Patient with depression taken antidepressants and responded well in the past also medicines effectively treated family member(s) is one factor to consider antidepressants for treatment. Also, antidepressants have chosen for the treatment of MDD with its efficacy of treating acute episodes and preventing relapses. The previous literature on meta-analysis reviews indicated continuing treatment with SSRIs reduces the risk of relapse, and the continuing treatment of SSRIs reduces the risk for another episode within the following year. Studies evidence that escitalopram has higher prophylactic efficacy; there are no significant differences between other SSRIs have evidenced. [18]. One of the previous literature on comparative study evidenced the efficacy in short-term response and remission of MDD between SNRI and SSRIs indicated SNRI is effective than SSRIs, in remission and response rates. [32] Sheehan and colleagues in their studies revealed venlafaxine and SSRIs to be equally as effective in the treatment of MDD. [34] Garnock-Jones and colleagues expressed differential views in their study they publicized SSRIs achieved a more rapid short-term response than venlafaxine. [20] Shreds of evidence in comparing venlafaxine with placebo indicated efficacy of venlafaxine at reducing relapse superior to placebo. However, further research is recommended to find the efficacy of reducing relapse between venlafaxine and other antidepressants. Also, pieces of evidence reveal TCAs are effective than SSRIs in reducing relapse. Though, the differences are not significant. [19] Additionally, TCA side effects would restrict their use to those patients who cannot tolerate SSRIs.

Table 1: shows antidepressants with relapse outcome analyzed in the reviewed literature

Antidepressants	Sample size	Measures	Relapse Rate	Articles referred
Sertraline 50-200mg [flexible dosage]	Major depressive disorder patients [n=185]		13%	Doogan DP and Caillard V.[1992]
Sertraline 50-150mg [flexible dosage]	Drug trail patients on week maintenance [n=117]	Sertraline	8.5%	Kamijima K et.al, [2006]
Sertraline 20-40mg [flexible dosage]	Drug trail patients on weekly treatment [n=353]	Sertraline	2%	Aberg-Wistedt A, et. al, [2000]
Paroxetine	Major depressive disorder: adult patients seen in OPD [N=133]	Paroxetine	9%	Anghelescu IG, et. al, [2006]
Fluoxetine	Depressed children and adolescents- trail patients [n=439]	Fluoxetine,	35%	Emslie GJ et. al, [2004]
Ecitalopram 10-20mg	Major depressive disorder patients [n=73]	Ecitalopram	27%	Kornstein SG, et.al, [2006]
[TCAs] Desipramine, Amitriptyline, Imipramine Mianserin,	Depressed patients with residual symptoms [n=40]	With CBT Without CBT	15% 35%	Fava GA, et.al, [1994]
[TCAs] Desipramine, Amitriptyline, Imipramine, Mianserin,	Depressed patients with residual symptoms [n=40]	With CBT Without CBT	35% 75%	Fava GA, et.al, [1996]
Fluoxetine, Mirtazapine, Mianserin, Amitriptyline, Tianeptine	Open label trail on MDD patients [n=60]	SSRI+SSRI	8.32%	Gulec. M, et.al, [2011]
Fluoxetine, SSRI	Patients on maintenance [n=10] Patients on remission [n=80]	-	8.9%	Dotoli D, et.al, [2006]
Fluoxetine, Ecitalopram, Sertraline ,Paroxetine SSRI with CBT	Patients with remission or responded to SSRI [n=387]	SSRI+CBT SSRI	41% 18%	Peselow ED, et.al, [2015]
Fluoxetine, Paroxetine, Sertraline	Naturalistic long term study on MDD patients [n=60]	SSRI	49%	Pundiak TM,et.al, [2008]

Shreds of evidence reveal adjunct of psychotherapy is beneficial in preventing future depression episodes in adults. [18] Cognitive behavior therapy has proven its significance in reducing relapses, using CBT with SSRIs is 35% whereas 70% SSRIs used alone in treating MDD. [29, 30] Cognitive abilities are under development in children, adolescents it is immature; thus, psychotherapy has proven not as effective as pharmacotherapy, particularly MDD patients with comorbid diagnoses. Hence, CBT is not suitable treatment in pediatric MDD. [7]

Data analysis indicates alternative treatment options for patients with MDD. There is a choice for patients who do not want to receive pharmacotherapy they can opt for long term CBT that benefit patients with no risk of side effects. Hence, patients opting adjunct treatment would be able to take optimal advantage of evidenced synergism available in the literature using a combined SSRI and CBT demonstrating its success. However, a patient unable to commit to CBT alternative is SSRIs. This review confirms one drug treating all the symptoms is decisive to determine the antidepressant is custom-made proportionality to the patient’s risk/benefit factors. The genetic screening found to be promising in maximizing the therapeutic benefits of antidepressants. However, literature studies futile to find any genetic markers associated with SSRI and its response in patients. [13] This study suggests that future research of MDD treatment aim at customizing comprehensive treatment for patients. Also, should focus on antidepressant therapy to achieve a specific response. However, research findings support to achieve full symptom remission with minimum or no symptoms. Also, improvements in the functional level of the patient with the quality of s life and also setting essential steps for the recovery should be a therapeutic goal. Hence, it is crucial to treat depression comprehensively with an adjunct approach to pharmacotherapy: such as pharmacotherapy and augmentation with psychotherapy, that is keen on improved quality of life and socio-occupational functioning of the patients.

CONCLUSION:

There are several reasons to compare outcomes for individual antidepressants across the studies. Analyzed reviews lack consensus on what constitutes a relapse. This review article analyzes the role of selective serotonin reuptake inhibitors and its effectiveness in preventing relapse of Major Depressive Disorder. Review analysis indicated positive effects of cognitive therapy in the relapse prevention of MDD. The Vittengl JR et al. study indicates the moderators of the continuation phase of cognitive therapy's effects on relapse, recurrence remission, and recovery from depression. SSRIs that continued further for one year reduce risk of MDD and relapse. Indeed, this fact evidences comparing extending SSRIs for a year measured across the alternative therapies in preventing MDD relapse. Escitalopram is proven to be better results with fewer side effects. The efficacy of SSRIs understood to have a similar affect that of TCAs and atypical antidepressants. The evidence supports continuing and maintaining antidepressant therapies in the long-term management of MDD indicated healthy, evidenced in shreds of mood disorders literature.4 The current review study conceptualizes that combination trials comparing antidepressants and psychotherapy more specifically CBT are significant in treatment decisions, to achieve remission, improve functioning and quality of life paving way to full recovery. [31]

Evidenced in one systematic review of 31 trials reported by Geddes and others (2003) indicated criteria for relapse differed in every trail. Indeed the results varied from poorly defined clinical criteria such as a change in treatment is indicated or increase in symptoms sufficient to warrant admission to hospital and various depression scales. Other than differences in trial methodology patients’ personality, genetic background, socioeconomic factors, and other personal variables also shown to influence relapse, this review study also analyzed that the number of prior episodes, medical and psychiatric comorbidity, and the presence of residual symptoms that signifies the relapse rate of MDD [32]. The recurrent review extracted from the literature indicated that patient in continuous stress paves to the clinical and demographic factors, biological and psychological markers as risk factors for recurrence of MDD. [33, 34] Thus the current studies suggest the longitudinal controlled studies combining other psychotherapies, conceptualizing and establish the role of psychological markers, and optimizing the duration of antidepressant treatment that would predict the relapse in MDD.

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

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Received on 18.07.2019 Modified on 28.07.2019

Research J. Pharm. and Tech 2019; 12(8): 3818-3824.

DOI: 10.5958/0974-360X.2019.00654.1