Abstract
Background
Non-hormonal pharmacotherapies are widely used to manage depressive and anxiety symptoms in peri- and postmenopausal women, but comparative evidence across drug classes remains heterogeneous.
Objective
To systematically evaluate the efficacy and safety of non-hormonal pharmacological interventions for depressive and anxiety symptoms during the menopausal transition and postmenopause.
Methods
A systematic review of six databases and trial registries identified randomized and non-randomized studies evaluating SSRIs, SNRIs, gabapentinoids, and other pharmacotherapies. Due to substantial clinical and methodological heterogeneity, a structured Synthesis Without Meta-analysis (SWiM) approach was applied.
Results
A total of Thirty-one studies (n = 8,124 participants) were included. SNRIs showed more frequent positive effects on depressive symptoms compared with other pharmacological classes, while SSRIs demonstrated modest and variable effects. Gabapentinoids consistently improved vasomotor symptoms but showed limited and low-certainty effects on mood outcomes. Evidence for anxiety outcomes was inconsistent across all drug classes. Certainty of evidence ranged from very low to moderate.
Conclusions
Non-hormonal pharmacotherapies may provide benefit for mood symptoms during the menopausal transition and postmenopause, particularly SNRIs; however, conclusions are limited by heterogeneity, indirectness, and lack of head-to-head comparative trials.
Clinical trial number
Not applicable.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12888-026-08428-9.
Keywords: Menopause, Perimenopause, Depression, Anxiety, Non-Hormonal, Pharmacotherapy antidepressants, Systematic review
Introduction
Menopause is now viewed as both a biological reproductive shift and a critical period affecting mental health [1]. In menopause, in addition to physical symptoms like hot flashes, major neuroendocrine changes are linked to a greater vulnerability to depression and anxiety [2]. Epidemiological studies suggest that women are at greater risk of developing clinically significant mood symptoms during the menopausal transition compared with the premenopausal period [3]. These symptoms may adversely affect daily functioning, quality of life, interpersonal relationships, sleep quality, and occupational performance [1, 4].
A global meta-analysis (102 studies, 1.14 M women) confirms depression in 32% of premenopausal and 30% of postmenopausal women, and anxiety in 29% and 39%, respectively [5]. During the menopausal transition and postmenopause, major depression risk rises 2–4 times; 80% have Vasomotor symptoms (VMS), and frequent VMS correlates with higher depression (1.4–58%) and anxiety (2.2–52%) rates [6].
Unlike typical depression or anxiety, menopausal mood changes have a unique biological basis driven by falling/fluctuating estrogen that directly alters serotonin, noradrenaline, and GABA [7]. By uniquely altering neurotransmitter balance and emotional/stress/sleep circuits, estradiol withdrawal reduces mood resilience, setting menopausal mood disturbances apart biologically from typical depression and anxiety [8]. The mechanism confirms menopausal depression/anxiety are biologically mediated and may show differential responses to standard psychiatric treatments.
Menopausal hormone therapy (MHT) can effectively alleviate mood symptoms for some women, particularly during early perimenopause [9]. A recent real world cohort study of 920 women showed that MHT initiation was associated with a 44.6% reduction in mood symptom scores after an average of 107 days [10]. Many women avoid hormone therapy either due to medical risks or lingering safety fears stemming from the WHI study [11, 12].
Despite the widespread use of non-hormonal pharmacotherapies for depressive and anxiety symptoms in midlife women, the evidence base remains fragmented and methodologically heterogeneous. Several studies evaluating antidepressants in women across the menopausal transition have enrolled mixed populations without consistently stratifying participants according to menopausal stage, thereby limiting interpretation of stage-specific treatment effects [13]. Similarly, although VMS are strongly associated with mood disturbances during the menopausal transition [2], relatively few trials have explicitly examined whether VMS burden modifies antidepressant response [13]. Furthermore, adverse events are frequently reported using general psychiatric safety outcomes rather than outcomes particularly relevant to midlife women, such as sexual functioning, sleep quality, weight change, and treatment discontinuation related to menopausal symptoms [2, 12, 14]. Finally, Lack of head-to-head trials on non-hormonal drugs for menopause-related mood issues leaves clinicians unsure which treatment works best [15].
This review focused on non-hormonal pharmacotherapies that have been evaluated for depressive and anxiety symptoms, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentinoids, bupropion, and mirtazapine. Interventions primarily investigated for vasomotor symptom management, such as oxybutynin and neurokinin receptor antagonists, were outside the scope of the review unless mood-related outcomes were reported.
Methods
Study design and registration
This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement [Supplementary Table S1]. Owing to anticipated clinical and methodological heterogeneity across studies, findings were synthesized narratively in accordance with the Synthesis Without Meta-analysis (SWiM) reporting guideline.
Eligibility criteria
Randomized and non-randomized intervention studies were eligible for inclusion if they enrolled women in the late reproductive stage, menopausal transition, or postmenopausal period who experienced depressive symptoms, anxiety symptoms, major depressive disorder, anxiety disorders, or other clinically significant mood disturbances, and evaluated the effects of a non-hormonal pharmacological intervention.
Menopausal status was accepted as defined by the original study authors. Methods used to classify menopausal stage varied across studies and included menstrual history, reproductive aging criteria, hormonal assessments, and established staging frameworks when reported.
Depression and anxiety were identified using a range of diagnostic approaches, including structured clinical interviews based on recognized diagnostic criteria, clinician-confirmed diagnoses, and validated symptom-assessment instruments. Eligible studies were required to assess depressive and/or anxiety outcomes using established diagnostic criteria or validated measurement tools, including but not limited to the Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale (HADS), and other standardized instruments.
Studies evaluating menopausal hormone therapy or other hormonal interventions, studies in which non-pharmacological interventions constituted the primary treatment, case reports, conference abstracts, narrative or systematic reviews, and animal studies were excluded.
Information sources and search strategy
A comprehensive and systematic literature search was conducted in six electronic databases, including PubMed/MEDLINE, Embase, Scopus, Web of Science Core Collection, PsycINFO, and CINAHL Complete, from database inception to February 1, 2025. To minimize publication bias and identify ongoing or unpublished studies, clinical trial registries, including ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), were also searched.
The search strategy was developed in consultation with the research team and combined controlled vocabulary terms (e.g., Medical Subject Headings [MeSH] and Emtree terms) with free-text keywords related to menopause, menopausal transition, postmenopause, depressive symptoms, depressive disorders, anxiety symptoms, anxiety disorders, and non-hormonal pharmacological interventions. The PubMed search strategy was developed first and subsequently adapted for the syntax and indexing systems of the other databases, including Embase, Scopus, Web of Science Core Collection, PsycINFO, and CINAHL Complete.
No restrictions were applied with respect to language, publication date, or geographic location. Reference lists of all included studies and relevant review articles were manually screened to identify additional potentially eligible studies that may not have been captured through the electronic database searches.
The complete search strategies for all databases, including database-specific controlled vocabulary terms, Boolean operators, truncation symbols, and search limits, are provided in Supplementary Table S2.
Study selection and data extraction
All records were imported into Covidence for study management and screening. Two reviewers (MH and MA) independently screened titles and abstracts, followed by full-text assessment of potentially eligible studies. Any disagreements were resolved through discussion and, when necessary, consultation with a third reviewer (ZBK). Inter-rater agreement for full-text eligibility assessment was excellent (κ = 0.87).
Data extraction was conducted independently by the same reviewers using a standardized and piloted extraction form. Extracted information included study design, participant characteristics, menopausal stage, methods used to classify menopausal status, diagnostic tools for depression and anxiety, diagnostic thresholds where reported, intervention characteristics, comparator type (placebo, active comparator, usual care, or no treatment), outcome measures, adverse events, duration of follow-up, and main study findings.
Information on VMS outcomes and the methods used to assess VMS was also extracted when reported in the original studies. In addition, data on concomitant treatments were collected where available. However, reporting of concurrent non-pharmacological interventions including cognitive behavioral therapy (CBT), psychotherapy, behavioral interventions, and other supportive approaches was inconsistent across studies.
Quality assessment
The methodological quality of the included studies was independently assessed by two reviewers.
For randomized controlled trials (RCTs), risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool, which assesses bias arising from the randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting. For non-randomized studies, the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was applied. Any disagreements between reviewers were resolved through discussion and consensus, with involvement of a third reviewer when necessary. The certainty of evidence for outcomes with sufficient data was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This framework evaluates evidence across five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. The certainty of evidence was classified as high, moderate, low, or very low. Detailed GRADE evidence profiles and Summary of Findings in Supplementary Table S3.
Synthesis approach and data synthesis
Given substantial heterogeneity across study populations, interventions, and outcome measures, meta-analysis was deemed inappropriate. Accordingly, a structured SWiM approach was employed.
Studies were grouped according to pharmacological class. Within each group, findings were synthesized based on the direction of effect relative to comparators, rather than pooled quantitative estimates. No inference was made based solely on statistical significance. However, greater interpretive weight was assigned to larger randomized trials and studies judged to be at low risk of bias, in line with SWiM guidance. Vote counting based on direction of effect was used exclusively as a descriptive tool and was not considered a proxy for effect size or treatment magnitude [Supplementary Table S4].
An a priori plan for meta-analysis had been established; however, quantitative synthesis was not undertaken due to extensive clinical and methodological heterogeneity. Sources of heterogeneity included variation in pharmacological agents, dosing regimens, participant characteristics, menopausal stage classification, diagnostic criteria for depression and anxiety, outcome measures, comparator types, assessment methods for VMS, and duration of follow-up.
Consequently, findings were synthesized narratively in accordance with SWiM reporting standards [Supplementary Table S5]. Studies were organized by intervention class, and where available, results were additionally described according to menopausal stage and VMS status. Given inconsistent reporting and limited stratified analyses, interpretations related to menopausal stage were made cautiously.
The primary synthesis focused on the direction, consistency, and relative magnitude of treatment effects across studies. Vote counting by direction of effect was used only as a supplementary descriptive method and was not used to draw inferential conclusions, consistent with SWiM recommendations.
Studies were categorized as showing beneficial effects, no clear effects, or mixed findings relative to comparators. Interpretation was informed not only by statistical significance but also by effect estimates, risk-of-bias assessments, sample size, and methodological robustness. Where conflicting evidence was present, greater interpretive emphasis was placed on studies with lower risk of bias, larger sample sizes, and more rigorous designs.
Sources of heterogeneity including menopausal stage, baseline symptom severity, VMS burden, comparator type, and outcome measurement methods were explored narratively. No formal indirect comparisons between intervention classes were conducted. Furthermore, subgroup analyses and head-to-head comparisons between pharmacological classes were not feasible due to the limited number of studies within several categories and the absence of direct comparative evidence.
Results
Study selection and characteristics
The systematic search across six electronic databases and clinical trial registries identified a total of 5,876 records. After removing duplicates (n = 3,124), 2,752 records were screened at the title and abstract level. Of these, 229 full-text articles were assessed for eligibility, and ultimately 31 studies met the inclusion criteria and were included in the final synthesis. The study selection process is reported in accordance with PRISMA 2020 guidelines (Fig. 1).
Fig. 1.
PRISMA 2020 flow diagram
The most common reasons for exclusion at the full-text screening stage included: (1) non-randomized design or absence of a control group, (2) lack of validated instruments for assessing depressive or anxiety symptoms, (3) irrelevance of the pharmacological intervention, and (4) study populations outside the menopausal transition or postmenopausal period.
The included studies were clinically heterogeneous and encompassed women across the full spectrum of the menopausal transition, including perimenopausal and postmenopausal stages, and in some cases women with primary depressive or anxiety disorders. All studies assessed mood-related outcomes using validated instruments, including the Hamilton Depression Rating Scale (HAM-D), the Montgomery - Åsberg Depression Rating Scale (MADRS), the BDI, the HAM-A, the Greene Climacteric Scale (GCS), and the Menopause-Specific Quality of Life Questionnaire (MENQOL).
The studies were grouped according to the pharmacological class of interventions. Among the included studies, 12 evaluated SSRIs, 12 investigated SNRIs, 3 assessed gabapentinoid agents, 2 examined fezolinetant, and 2 evaluated herbal interventions. Studies were also categorized based on whether depression and/or anxiety outcomes were defined as primary or secondary endpoints. Studies primarily focusing on VMS or quality of life were summarized in Supplementary Tables S6-S8.
Given substantial clinical and methodological heterogeneity, quantitative synthesis (meta-analysis) was deemed inappropriate, and findings were therefore synthesized narratively in accordance with SWiM guidelines.
Formal assessment of publication bias was not feasible, as no meta-analysis was conducted and the number of studies within each intervention category was limited.
Risk of bias assessment
Risk of bias in randomized controlled trials was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Overall, most studies were judged to have either a low risk of bias or some concerns. The most common sources of bias were deviations from intended interventions and incomplete outcome data reporting. In contrast, non-randomized or open-label studies were generally considered to have a serious risk of bias, primarily due to confounding and the absence of blinding. Detailed risk of bias assessments is presented in Supplementary Table S4.
Certainty of evidence (GRADE)
The certainty of evidence, as assessed using the GRADE approach, ranged from very low to moderate across outcomes (Supplementary Table S3). Certainty ratings were limited to studies that directly reported the outcome of interest, whereas vote-counting included all eligible studies contributing to the overall direction-of-effect synthesis. Evidence for SSRIs on depressive symptoms was rated as moderate certainty, whereas evidence for their effects on anxiety symptoms was rated as low certainty. For SNRIs, the certainty of evidence was moderate for depressive symptoms and ranged from low to moderate for anxiety symptoms. In contrast, evidence for gabapentinoids was rated as very low certainty for depressive and anxiety symptoms, although it was rated as moderate certainty for VMS. For fezolinetant, the certainty of evidence for psychosocial outcomes was low. Finally, evidence regarding herbal interventions was rated as very low certainty.
SSRIs
A total of 12 studies evaluated SSRIs, including paroxetine, escitalopram, citalopram, sertraline, and fluoxetine (Table 1; Supplementary Table S6).
Table 1.
SSRIs for depressive and anxiety symptoms during the menopausal transition and postmenopause
| Author (Year) | Country | Design | N | Population / Menopausal Stage | Intervention | Comparator | Mood Assessment Tool | Diagnostic Criteria | Duration | Primary Outcome(s) | Key Findings |
|---|---|---|---|---|---|---|---|---|---|---|---|
|
Soares et al. (2008) [16] |
Canada | RCT | 100 | Perimenopausal and menopausal women (STRAW criteria) with depressive symptoms | Paroxetine CR 12.5–25 mg/day | Placebo | MADRS | DSM-IV depressive disorder | 8 weeks | Depressive symptoms | Significant reduction in depressive symptom severity compared with placebo. |
| DeFronzo-Dobkin et al. (2009) [17] | USA | Pilot RCT | 22 | Healthy peri- and postmenopausal women | Escitalopram 10–20 mg/day | Placebo | MENQOL, GCS | Menopausal symptoms | 8 weeks | Mood-related and quality-of-life outcomes | Improvements in MENQOL and psychological symptom scores; findings limited by small sample size. |
| Freeman et al. (2011) [18] | USA | Multicenter RCT | 205 | Peri- and postmenopausal women with menopausal symptoms | Escitalopram 10–20 mg/day | Placebo | Anxiety, mood and QoL measures | Symptomatic peri/postmenopause | 8 weeks | Depression, anxiety, quality of life | Significant improvements in mood, anxiety, and quality-of-life outcomes compared with placebo. |
| Masoumi et al. (2016) [14] | Iran | Triple-blind RCT | 60 | Postmenopausal women with depression | Citalopram 20 mg/day + Omega-3 (1 g/day) | Citalopram + placebo | BDI | DSM-IV depression | 4 weeks | Depressive symptoms | Significant reduction in BDI scores at weeks 2 and 4 compared with control (p < 0.001). |
Abbreviations: BDI, Beck Depression Inventory; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; GCS, Greene Climacteric Scale; MADRS, Montgomery–Åsberg Depression Rating Scale; MENQOL, Menopause-Specific Quality of Life Questionnaire; QoL, Quality of Life; RCT, Randomized Controlled Trial
Effects on depressive symptoms
Among the included SSRI studies, several directly assessed depressive symptoms using validated depression rating scales, whereas others reported mood-related outcomes as secondary endpoints. Overall, SSRIs were associated with improvements in depressive symptoms, although the magnitude and consistency of effects varied across studies.
Paroxetine demonstrated the most consistent evidence for reducing depressive symptom severity. For example, Soares et al. reported significantly greater reductions in MADRS scores among women receiving paroxetine compared with placebo during the menopausal transition. Similarly, Masoumi et al. observed greater improvements in BDI scores among participants treated with citalopram in combination with omega-3 supplementation than among those receiving the comparator intervention.
Studies evaluating escitalopram also reported improvements in depressive symptoms and psychological well-being. However, variability in study populations, outcome measures, and treatment durations limited direct comparisons across trials. Overall, the available evidence suggests that SSRIs may confer modest benefits for depressive symptoms in peri- and postmenopausal women, although the certainty of evidence remains moderate.
Effects on anxiety symptoms
Anxiety outcomes were assessed less frequently and with greater variability than depressive outcomes. Some studies, particularly those evaluating escitalopram, reported improvements in anxiety-related symptoms and psychosocial functioning. However, several trials found limited or non-significant effects on anxiety measures.
Overall, evidence regarding the anxiolytic effects of SSRIs in peri- and postmenopausal women was inconsistent, and most findings were derived from secondary outcome analyses rather than studies specifically designed to evaluate anxiety disorders. Consequently, the certainty of evidence for anxiety outcomes was considered low.
Studies primarily evaluating vasomotor symptoms
Several SSRI trials primarily investigated VMS and menopause-related quality of life rather than mood outcomes (Supplementary Table S6). Across these studies, paroxetine consistently reduced the frequency and severity of hot flashes and was associated with improvements in psychosocial functioning and menopause-related quality of life. Findings for other SSRIs were more variable.
Although improvements in mood-related outcomes were frequently observed alongside reductions in VMS burden, these outcomes were generally assessed as secondary endpoints. Therefore, while SSRIs appear to have favorable effects on psychosocial well-being and menopause-specific quality of life, direct evidence supporting their efficacy for depressive or anxiety disorders remains limited.
SNRIs
A total of 12 studies evaluated SNRIs, predominantly venlafaxine and desvenlafaxine (Table 2; Supplementary Table S7).
Table 2.
SNRIs for depressive and anxiety symptoms during the menopausal transition and postmenopause
| Author (Year) | Country | Design | N | Population / Menopausal Stage | Intervention | Comparator | Mood Assessment Tool | Diagnostic Criteria | Duration | Primary Outcome(s) | Key Findings |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Kornstein et al. (2010) [27] | USA | Randomized, placebo-controlled trial | 387 | Perimenopausal and postmenopausal women with MDD | Desvenlafaxine 100–200 mg/day | Placebo | HAM-D17 | DSM-IV MDD | 8 weeks | Depressive symptoms | Significant reduction in HAM-D17 scores and higher response/remission rates compared with placebo. |
| Clayton et al. (2013) [28] | USA | Randomized, placebo-controlled trial | 363 | Perimenopausal and postmenopausal women with MDD | Desvenlafaxine 50 mg/day | Placebo | HAM-D17, MADRS, QIDS-SR | DSM-IV MDD | 8 weeks | Depressive symptoms | Significant improvements in depressive symptoms and remission outcomes compared with placebo. |
| Kulkarni et al. (2018) [29] | Australia | Randomized controlled trial | 80 | Perimenopausal women with depression | Desvenlafaxine-based treatment | Comparator regimen | MADRS | Clinical diagnosis of depression | 6 months | Depressive symptoms | Significant reduction in depressive symptom severity during follow-up. |
| Schneider et al. (2013) [30] | USA | Randomized controlled trial | 130 | Postmenopausal women with depression | Desvenlafaxine | Placebo | MADRS | MDD | 8 weeks | Depressive symptoms | Reduction in depressive symptom burden relative to placebo. |
| caan et al. (2015) [31] | USA | Randomized placebo-controlled trial | 339 | Perimenopausal and early postmenopausal women | Oral 17β-estradiol 0.5 mg/day (n = 97) or Venlafaxine XR 75 mg/day (n = 96) | Placebo (n = 146) | PHQ-9 (depressive symptoms), GAD-7 (anxiety symptoms), Perceived Stress Scale (PSS) | No DSM diagnosis required; women with major depressive episodes or severe psychiatric illness were excluded | 8 weeks | Menopause-specific Quality of Life (MENQOL) | Neither treatment produced significant improvements in depressive symptoms (PHQ-9) or anxiety symptoms (GAD-7). |
| Mahajan et al. (2022) [32] | India | Randomized, Open-label, Intention-to-Treat Trial | 40 | Postmenopausal women (40–65 years; natural or surgical menopause) with newly diagnosed depression and anxiety | Desvenlafaxine 50–100 mg/day | Escitalopram 10–20 mg/day | HAM-D | Clinical diagnosis of depression | 6 weeks | Depressive symptoms | Both groups improved; no clear superiority established. |
| Davari-Tanha et al. (2016) [33] | Iran | Randomized controlled trial | 60 | Postmenopausal women | Venlafaxine 75 mg/day | Citalopram and placebo | BDI | Postmenopausal depressive symptoms | 8 weeks | Depressive symptoms | No significant difference among study groups. |
Abbreviations: BDI, Beck Depression Inventory; HAM-D, Hamilton Depression Rating Scale; MADRS, Montgomery Åsberg Depression Rating Scale; MDD, Major Depressive Disorder; MENQOL, Menopause-Specific Quality of Life Questionnaire; QIDS-SR, Quick Inventory of Depressive Symptomatology Self Report
Effects on depressive symptoms
Most SNRI studies reported improvements in depressive symptoms relative to placebo or comparator interventions. Desvenlafaxine demonstrated the most consistent evidence, with studies by Kornstein et al. and Clayton et al. reporting significant reductions in Hamilton Depression Rating Scale (HAM-D) scores and higher remission rates compared with control groups. Similar findings were observed in studies conducted by Schneider et al. and Kulkarni et al.
In contrast, Davari-Tanha et al. reported no statistically significant differences between venlafaxine and comparator groups. Nevertheless, the overall direction of effect across studies favored SNRIs, which demonstrated the most consistent antidepressant effects among the pharmacological classes evaluated in this review. The certainty of evidence for depressive outcomes was rated as moderate.
Effects on anxiety symptoms
Anxiety outcomes were evaluated in a smaller number of studies and were rarely designated as primary endpoints. Nevertheless, available evidence generally favored SNRIs. For example, Joffe et al. reported improvements in psychosocial functioning and anxiety-related domains among women receiving venlafaxine.
Despite these findings, the limited number of studies specifically designed to assess anxiety symptoms restricts confidence in conclusions regarding direct anxiolytic efficacy. Consequently, the certainty of evidence for anxiety outcomes ranged from low to moderate.
Studies primarily evaluating vasomotor symptoms
Several SNRI studies primarily focused on vasomotor symptoms and menopause-related quality of life (Supplementary Table S7). Across these trials, desvenlafaxine consistently reduced the frequency and severity of hot flashes and improved quality-of-life measures. Improvements in psychosocial functioning frequently accompanied reductions in vasomotor symptom burden, suggesting a potential indirect contribution to emotional well-being.
Gabapentinoids
Three studies evaluated gabapentinoids, including two trials of gabapentin and one trial of pregabalin (Table 3, Supplementary Table S8).
Table 3.
Other non-hormonal pharmacotherapies for depressive and anxiety symptoms during the menopausal transition and postmenopause
| Author (Year) | Country | Design | N | Population / Menopausal Stage | Intervention Details | Control Group | Mood Assessment Tool | Diagnostic Criteria | Duration | Primary Outcome(s) | Key Findings |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Rickels et al. (2005) [39] | USA | RCT | 276 | Women with GAD (not menopause-specific) | Pregabalin 150–600 mg/day | Placebo | HAM-A | DSM-IV | 4 weeks | HAM-A | Significant anxiolytic effect (not menopause-specific) |
Effects on depressive and anxiety symptoms
Evidence regarding the effects of gabapentinoids on mood symptoms was limited and heterogeneous. Some studies reported improvements in sleep quality and reductions in anxiety-related distress with gabapentin treatment; however, depressive symptoms were generally not assessed as primary outcomes. Pregabalin demonstrated anxiolytic efficacy in populations with generalized anxiety disorder, although the available evidence was not specific to menopausal women.
Overall, evidence supporting the use of gabapentinoids for depressive or anxiety symptoms in peri- and postmenopausal women was indirect and of very low certainty.
Effects on vasomotor symptoms
All included gabapentinoid studies reported reductions in the frequency and severity of vasomotor symptoms compared with placebo or active comparators. The consistency of findings across studies supports moderate-certainty evidence for the effectiveness of gabapentinoids in managing vasomotor symptoms in menopausal women.
Other non-hormonal pharmacotherapies
Four studies evaluated other non-hormonal pharmacological interventions, including two studies of fezolinetant and two studies investigating herbal therapies. Fezolinetant was associated with improvements in menopause-related quality of life and psychosocial well-being; however, mood-related outcomes were generally assessed as secondary endpoints. Evidence for herbal interventions was mixed. One study reported no significant differences between treatment groups, whereas another demonstrated modest improvement when herbal therapy was combined with pharmacological treatment.
Overall, the evidence supporting these interventions remained limited, and the certainty of evidence ranged from low to very low.
For bupropion and mirtazapine, only single studies with small sample sizes and methodological limitations were identified; therefore, no reliable estimates of efficacy for depressive or anxiety symptoms could be derived, and these agents were not analyzed separately (Table 3, Supplementary Table S8).
Discussion
This systematic review synthesizes evidence from 31 studies on non-hormonal pharmacotherapies for depressive and anxiety symptoms during the menopausal transition and postmenopause.
SSRIs showed modest and heterogeneous effects on depressive symptoms, with more consistent signals in postmenopausal populations [46, 47]. Effects on anxiety were inconsistent and largely based on secondary outcomes, limiting interpretability. Overall, SSRIs demonstrated low-to-moderate efficacy for depressive symptoms and uncertain effects on anxiety, with variability likely driven by differences in population characteristics, outcome selection, and menopausal stage [46].
SNRIs demonstrated the most consistent evidence of benefit for depressive symptoms across studies, with supportive findings also for anxiety and quality-of-life–related outcomes, particularly in women with prominent VMS [38]. The co-occurrence of mood symptoms and VMS may reflect overlapping neurobiological pathways involving estrogen-sensitive serotonergic and noradrenergic systems [48–50]. However, in the absence of head-to-head comparisons, these findings should be interpreted as consistency of benefit rather than comparative superiority.
SNRIs were associated with higher discontinuation rates and more frequent adverse effects, including gastrointestinal symptoms, sweating, and blood pressure increases, which may restrict use in women with cardiometabolic comorbidity [51].
Evidence for gabapentinoids was limited and primarily VMS-focused. While moderate-certainty evidence supports efficacy for VMS reduction, evidence for depressive and anxiety symptoms was very low and inconsistent [52]. Any observed mood benefit appears secondary to VMS improvement rather than direct psychotropic effects. Sedation and dizziness further limit their utility in long-term management [53].
Evidence for bupropion, mirtazapine, clonidine, fezolinetant, and herbal preparations was sparse and of low to very low certainty. Although isolated studies suggest potential benefits for depressive symptoms or quality of life, methodological limitations and small sample sizes preclude robust conclusions [46, 47]. These interventions remain insufficiently studied in menopausal mood disorders.
Potential effect modifiers, including menopausal stage and VMS burden, may influence treatment response. SSRIs appeared more effective in postmenopausal women, whereas SNRIs showed greater effects in those with prominent VMS. However, inconsistent stratification and lack of formal interaction analyses limit inference, and these findings should be considered hypothesis-generating.
Overall, this review highlights heterogeneous but clinically meaningful signals of benefit across pharmacological classes, with SNRIs showing the most consistent effects on depressive symptoms. However, certainty of evidence remains low to moderate, and the absence of direct comparative trials limits conclusions regarding relative efficacy. Future research should prioritize adequately powered head-to-head trials, standardized outcome frameworks, and stratification by menopausal stage and VMS burden to enable precision treatment strategies in midlife women.
Limitations
This review has several limitations. First, substantial clinical and methodological heterogeneity precluded meta-analysis and limits the precision of conclusions. Second, included studies varied in their definition of menopausal status and in whether mood symptoms were primary or secondary outcomes. Third, differences in measurement tools and diagnostic approaches contributed to heterogeneity in outcome assessment.
Fourth, the absence of head-to-head trials prevents conclusions regarding comparative effectiveness between pharmacological classes. Fifth, the narrative synthesis approach is inherently interpretive; however, efforts were made to reduce subjectivity by prioritizing larger and lower risk-of-bias studies in interpretation.
Conclusion
Non-hormonal pharmacotherapies may improve depressive and anxiety symptoms in peri- and postmenopausal women, but effects are variable across drug classes and outcomes. SNRIs show the most consistent benefit for depressive symptoms, particularly in women with vasomotor symptoms, while SSRIs demonstrate mixed effects and gabapentinoids are more effective for vasomotor symptoms than for mood.
Evidence for other agents (bupropion, mirtazapine, clonidine, fezolinetant, and herbal treatments) is limited and inconclusive. Overall certainty of evidence is low to moderate, and heterogeneity limits firm comparative conclusions. These findings are hypothesis-generating, and treatment should be individualized until higher-quality head-to-head trials are available.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the university health sciences librarian who assisted with the search strategy.
Author contributions
M.A participated in data collection and drafting and editing of the paper. Z.B.K participated in data analysis and revision of the paper. M.H participated in data interpretation and critical review of the manuscript. All authors saw and approved the final version and no other person made a substantial contribution to the paper.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Declarations
Ethics, consent to participate, and consent to publish
Not applicable in the manuscript.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
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