Abstract
Rationale
Selective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders. However, which aspects of anxiety are affected by SSRIs is not yet fully understood.
Objective
We aimed to systematically review the effect of six clinically effective SSRIs on four aspects of unconditioned anxiety: approach-avoidance behaviour (elevated plus maze), repetitive behaviour (marble burying), distress behaviour (ultrasonic vocalization), and activation of the autonomous nervous system (stress-induced hyperthermia).
Methods
We identified publications by searching Medline and Embase databases and assessed the risk of bias. A random effects meta-analysis was performed and moderator effects were analysed with Bayesian penalized meta-regression.
Results
Our search yielded 105 elevated plus maze, 63 marble burying, 11 ultrasonic vocalization, and 7 stress-induced hyperthermia articles. Meta-analysis suggested that SSRIs reduce anxiety-like behaviour in the elevated plus maze, marble burying and ultrasonic vocalization test and that effects are moderated by pre-existing stress conditions (elevated plus maze) and dose dependency (marble burying) but not by duration of treatment or type of SSRI. The reporting quality was low, publication bias was likely, and heterogeneity was high.
Conclusion
SSRIs seem to reduce a broad range of unconditioned anxiety-associated behaviours. These results should be interpreted with caution due to a high risk of bias, likely occurrence of publication bias, substantial heterogeneity and limited moderator data availability. Our review demonstrates the importance of including bias assessments when interpreting meta-analysis results. We further recommend improving the reporting quality, the conduct of animal research, and the publication of all results regardless of significance.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Serotonin is known to play an important role in the development and treatment of anxiety-like disorders. These include various anxiety disorders but also obsessive-compulsive disorders and trauma- and stressor-related disorders and they are all paired with a feeling of intense distress. Selective serotonin reuptake inhibitors (SSRIs) are currently the first choice of pharmacological treatment for patients with anxiety-like disorders. However, the exact pathophysiology of anxiety-like disorders and the specific aspects of anxiety that are modulated by these SSRIs are not yet fully understood. Human studies suggest that SSRIs can improve fear extinction (Bui et al. 2013). Also, SSRI treatment in young people could increase the ability to regulate emotions, reduce anger processing, increase positive bias and reduce avoidance of social situations (Murphy et al. 2021). Better insight into how SSRIs specifically affect anxiety-like symptoms could be obtained by performing animal tests. By identifying the anxiety aspects that are affected by SSRIs, we will gain a better understanding of the role serotonin plays in approach-avoidance behaviour, repetitive behaviour, distress behaviour, and activation of the autonomous nervous system. This is interesting for multiple reasons, all relating to the possible identification of new therapeutic targets for patients with anxiety-like disorders. First of all, not all patients experience the therapeutic beneficial effects of SSRIs and therefore there is a need for alternative pharmacological treatments. Identification of anxiety tests in animals that do not show an anxiolytic effect of SSRIs provides an opportunity to investigate whether these tests reflect the SSRI non-responder patient group. Second, SSRIs are known for their delayed therapeutical onset in the treatment of anxiety-like disorders (Lenze et al. 2005; Rickels et al. 2003). Thus, patients do not experience an immediate relief of symptoms after starting treatment and sometimes will even experience a worsening of symptoms for a short period (Offidani et al. 2013). It is, therefore, interesting to investigate whether there are pharmacological treatments that show an acute anxiolytic response in SSRI-sensitive behavioural tests.
Here we build on our previous work in which we systematically reviewed the effect of six clinically-approved SSRIs on tests of conditioned anxiety. The results of this systematic review suggested that the clinical efficacy of SSRIs may be linked to their effects on contextual fear expression and extinction of cued fear (Heesbeen et al. 2023). However, these results did not exclude the possibility that SSRIs also generally inhibit fear-related emotions. A similar data synthesis of the effect of SSRIs on tests of unconditioned anxiety has not yet been carried out. Therefore, with this systematic review, we aimed to establish which aspects of unconditioned anxiety are sensitive to the six clinically-approved SSRIs. We set out to investigate the effect of SSRIs on four aspects of unconditioned anxiety: approach-avoidance behaviour, repetitive behaviour, distress behaviour, and activation of the autonomous nervous system. These aspects are tested in the elevated plus maze, marble burying test, ultrasonic vocalization test, and stress-induced hyperthermia test, respectively.
The initial animal tests that were developed to investigate anxiolytic drug effects were based on the experimentally induced conflict between approach and avoidance behaviour. The elevated plus maze is based on this principle and is most commonly used for anxiolytic drug screening (Ravi and Eerike 2022), and was therefore selected for this review instead of other approach-avoidance tests such as the light-dark box. Rodents experience a conflict between exploring the open arms (approach) and fearing the open arms and thus favouring the enclosed arms (avoidance) (Pellow et al. 1985). This conflict of approach and avoidance is an important concept of human anxiety and individuals with anxiety-like disorders typically show increased avoidance behaviour. Another way to assess anxiolytic drug efficacy is by performing the ultrasonic vocalization test. This test is based on the principle that aversive events (e.g. separation from littermates, electric shock, mild restraint stress) in neonatal or adult rodents induce distress behaviour which manifests in ultrasonic vocalizations (USVs) (Cuomo et al. 1988); Gardner 1985; Winslow and Insel 1991a; b). The number of emitted USVs indicates the stress that is experienced by individuals with anxiety after exposure to unavoidable aversive situations (Jelen et al. 2003). Anxiolytic drug efficacy can also be assessed in the stress-induced hyperthermia test, which assesses the increase in body temperature after exposure to a stressor, as a proxy of activation of the autonomic nervous system. Since stress leads to consistent body temperature changes in humans, body temperature as measured in the stress-induced hyperthermia test remains a good physiological readout of a stress response (Vinkers et al. 2013). In addition to the aforementioned anxiety aspects, it is also possible to measure the persistent and repetitive behaviour of animals with the marble burying test which is based on the naturally occurring tendency of rodents to bury objects situated in their environment (De Boer and Koolhaas 2003; Poling et al. 1981). This behaviour is thought to be more ethologically relevant to obsessive-compulsive disorder than to other anxiety-like disorders since the repetitive behaviour resembles the stereotype pattern behaviour that is often observed in obsessive-compulsive patients (Thomas et al. 2009; Witkin 2008).
In addition to reviewing the effects of SSRIs in these four tests, we performed moderator analyses to determine whether the effects of SSRIs were dependent on the type of SSRI under study and the duration of treatment, the presence of a pre-existing anxiety condition, sex differences and the species under study. The results of the moderator analysis could help to optimize the experimental set-up for studying unconditioned anxiety.
Materials and methods
This systematic review was written according to the guidelines as described in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (Page et al. 2021).
Study protocol
This systematic review was performed according to a preregistered protocol (PROSPERO, CRD42022371871) which was registered on 16 December 2022 and can be accessed through this website: https://www.crd.york.ac.uk/prospero/.
Literature search and selection
Search strategy
A literature search was performed in two large medical databases: Medline and Embase. The search contained all articles published up until the 12th of September 2022. The search strategy was based on the following three components: (1) anxiety test (elevated plus maze or marble burying or ultrasonic vocalization or stress-induced hyperthermia); (2) clinically effective SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline); and (3) all animals (animal filters from Hooijmans et al. (2010) and de Vries et al. (2014)). We conducted four separate searches, one for each anxiety test. The specific search string for the animal test was combined with the second and third search components. The complete search string can be found in Supplementary file S1. The four sets of articles that were obtained through this search were imported and deduplicated in Endnote. The web program Rayyan (https://www.rayyan.ai/) was subsequently used to perform the study selection on the remaining articles.
Study selection
All articles obtained through the literature search were screened independently by two reviewers (TvK and EH) according to the inclusion (Table 1) and exclusion criteria (Table 2) as described in the preregistered protocol. Two screening phases took place: (1) screening of the titles and abstracts of all the unique articles; (2) screening of the full text of possibly relevant articles to determine eligibility. Any discrepancies that occurred in the screening phases were resolved by a discussion between the two reviewers, a third reviewer (EYB or LG) was only consulted whenever the conflict could not be resolved.
Extraction of study characteristics
The general and test-specific characteristics as summarized in Table 3 were extracted from the included articles by one reviewer (TvK) and checked by the second reviewer (EH).
Risk of bias assessment
SYRCLE’s risk of bias tool was used to assess the study quality of all included articles (Hooijmans et al. 2014). This tool uses the following three ratings: high, unclear, or low risk of bias. The risk of bias was scored as “low” whenever an article took proper measures to minimise or prevent the risk of bias. However, articles that did not take sufficient measures to limit the risk of bias were scored as “high” (e.g., researchers were not blinded for the experimental conditions). If data was insufficient to evaluate the risk of bias, the respective items of the risk of bias tool were scored as “unclear”. In this tool, six general categories are distinguished to assess the risk of bias, namely: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases. Within the latter category, the presence of a conflict of interest was assessed for every article. Two steps were taken to assess “selective outcome reporting” (reporting bias): (1) checking whether the outcome measures mentioned in the method section were also reported in the result section and (2) determining whether the preclinical studies were preregistered by examining the following two databases: Animal Study Registry (https://www.animalstudyregistry.org) and Preclinicaltrials (https://preclinicaltrials.eu/database). We added two additional reporting items to the risk of bias tool to assess whether any randomization and blinding occurred within the experiment. Two reviewers (TvK and EH) independently assessed the risk of bias and discrepancies were resolved by discussion.
Extraction of outcome data
One reviewer (TvK) extracted the outcome data of the selected articles which was then checked by a second reviewer (EH). The specific outcome measures that were extracted differed per test: (percentage of) time and number of entries in open arm (elevated plus maze); number of marbles buried (marble burying); number and duration of ultrasonic vocalizations (ultrasonic vocalization); and baseline body temperature and difference in body temperature (stress-induced hyperthermia). For each anxiety test, only one outcome measure was extracted per animal to prevent dependency in our data set. The mean, standard deviation (SD) or standard error of the mean (SEM) and number of animals were extracted for both the SSRI and the control group. If the data that needed to be extracted was presented in a different unit than a mean with an SD/SEM (e.g., interquartile range or median), the data was converted by using the appropriate formulas under the assumption that the data was normally distributed. Data was extracted from text, tables, and figures. The latter data was extracted with a digital ruler. If the number of animals was presented as a range, the largest value was used to calculate the corresponding SD. When an article had missing or unclear data, the authors were contacted. If the authors in question could not provide the requested data, the article was removed from the meta-analysis.
Several different outcome measures were reported for the elevated plus maze within the selected articles. The order of importance of these outcome measures was determined based on the predefined estimated relevance of the observed anxiety-like behaviour. The outcomes were ranked as follows: (1) entries in open arms as a percentage of total entries (%EOA), (2) time spent in open arms as a percentage of total time spent in any of the arms (%TOA), (3) absolute number of entries in open arms (EOA) and (4) absolute amount of time spent in open arms (TOA). Articles not reporting any of these four outcome measures were individually evaluated to include the most relevant outcome measure in the analysis.
For the ultrasonic vocalization test, two types of outcome measures were reported by the selected articles: duration and number of vocalizations. The latter outcome measure was determined to be most relevant and thus if an article reported both outcome measures the number of vocalizations was extracted.
We also extracted the effect of SSRIs on locomotor activity from studies that used the elevated plus maze, marble burying and ultrasonic vocalization test. Locomotor activity was extracted from either the anxiety test, a locomotor test that was performed after the anxiety test of interest or a locomotor test that was performed on a separate group of animals. Since these tests rely on physical motor activity, drug effects on locomotor activity could influence the anxiety outcome measure. Descriptive outcome data was extracted as a significant increase/no effect/significant decrease in locomotor activity compared to the placebo-controlled group.
Data-analysis
Meta-analysis was performed in R (R Core Team 2023) using the R-packages metafor (Viechtbauer 2010) and pema (Van Lissa et al. 2023). The analysis code was preregistered to ensure reproducibility and transparency and can be found via: https://github.com/cjvanlissa/meta_anx_ssri.git. A random effects model was applied since variation in true effect size was expected. Each data set was analysed separately. Effect sizes were obtained through a three-level meta-analysis to account for dependent effect sizes within studies (e.g. due to multiple uses of the control group in dose-response studies) and presented as Hedges’ g with a 95% Confidence Interval (CI) (Van den Noortgate et al. 2015). If articles reported a sample size range, the lowest value was used to calculate the corresponding effect size.
Six categorical predefined moderators were coded to account for the between-studies heterogeneity: type of SSRI, duration of treatment, disease induction, species, sex, and use of pretest. Disease induction is defined as heightened anxiety-related behaviour of subjects due to either pharmacological, genetic or environmental manipulation. A pretest is a selection procedure for the anxiety test of interest to ensure that the animals included in the experiment are sensitive to the investigated anxiety test. For the ultrasonic vocalization and stress-induced hyperthermia, we defined an extra moderator, type of test, which was separation-induced and physical stress-induced for the ultrasonic vocalization and group or individual for the stress-induced hyperthermia. A total of 27 dummy variables were created to define all conditions within these categorical moderators (Table 4). A classical meta-regression model was not identified since the number of moderators was almost identical to the number of available effect sizes (per anxiety test). Therefore, Bayesian regularized meta-regression (BRMA), implemented in the pema package, was used (Van Lissa et al. 2023). BRMA performs moderator selection by shrinking small regression coefficients towards zero with the use of a horseshoe prior, which also aids model identification (Van Lissa et al. 2023). In addition to the categorical moderators, one continuous moderator was included in the analysis: the human equivalent dose (HED). The HED was calculated from the reported dose by using species-specific conversion factors which are based on body surface area (Center for Drug Evaluation and Research 2005, available at: http://www.fda.gov/downloads/Drugs/Guidance/UCM078932.pdf).
The BRMA requires the selection of reference categories to examine the effect of the categorical variables. Dummy variables encode the difference between each remaining category and this reference category. When examining the results, the intercept represents the expected effect size for a study that falls within the reference category for all categorical variables. The effect of dummy variables represents the difference between that category with the reference category. If a dummy variable has a significant effect, that means that that group’s mean differs significantly from the reference category’s mean (i.e., from the intercept). The reference categories for each data set are reported in Table 5. The combination of these reference categories was predicted to yield the greatest anxiolytic effect of SSRIs and was therefore chosen. Note that in penalized regression, predictors are usually standardized. However, the effect of standardized dummies cannot be meaningfully interpreted. Therefore, only continuous predictors were standardized in this analysis. This may give dummy variables a slight advantage, leading them to become significant sooner than continuous ones.
Publication bias was assessed via visual inspection of funnel plots, and analysis of the Egger’s regression test and the likelihood ratio test (Satish and Joel 1988). Funnel plots were created by plotting the standardized mean difference (SMD) against the standard error. Asymmetry of the funnel plots was taken as a risk for publication bias and assessed by visual inspection. Egger’s regression test is a linear regression of the effect sizes on their standard errors, weighted by their inverse variance. A regression slope of zero is expected in the absence of publication bias (Lin and Chu 2018). We conducted likelihood ratio tests (LRT) to examine whether there was evidence that publications with a p-value < 0.05 were more likely to be published. Note that these methods for detecting publication bias are only valid for random effects models; they thus ignore the multilevel structure of the data.
Results
Data documentation
The Workflow for Open Reproducible Code in Science (WORCS) (Van Lissa et al. 2021) was used to make all analysis code and synthetic data available in a reproducible GitHub repository (https://doi.org/10.17605/OSF.IO/3WD8C). A complete overview of the study characteristics of all included studies can be found in Supplementary file S2.
Study selection
The Medline and Embase databases were systematically searched for relevant literature, which yielded 906 unique articles for the elevated plus maze, 627 unique articles for the marble burying, 251 unique articles for the ultrasonic vocalizations and 53 unique articles for the stress-induced hyperthermia. After full-text screening, the number of articles included in the systematic review/meta-analysis, respectively, was: 105/100 (elevated plus maze), 63/61 (marble burying), 11/11 (ultrasonic vocalizations) and 7/6 (stress-induced hyperthermia). The detailed selection procedures per anxiety test are visualized in flowcharts (Fig. 1).
Summary of effects of SSRIs on unconditioned anxiety
The overall effect sizes of the four anxiety tests are shown in Fig. 2. Results of both the classical meta-regression and the BRMA can be found in Supplementary file S3. As shown in Fig. 2 the estimated pooled effect sizes of the four anxiety tests indicated that SSRIs reduce anxiety-like behaviour in the elevated plus maze, marble burying and ultrasonic vocalization tests but not in the stress-induced hyperthermia test. The forest plots showing the effect sizes of the individual experiments can be found in Figs. 3, 4, 5 and 6. Below, we describe the descriptive statistics and the meta-analysis for each anxiety test separately. We only reported moderator effects whose 95% credible interval excluded zero. This interval is the Bayesian counterpart of statistical significance since there is a 95% probability that it contains the population effect size.
Elevated plus maze
Descriptive statistics
The effect of SSRIs on the elevated plus maze test was investigated in 241 unique experiments (105 articles). Fluoxetine was the most studied SSRI (n = 60), the other SSRIs were studied to a lesser extent (Table 6). Acute SSRI administration (n = 48) and subchronic SSRI administration (n = 59) dosing regimens were most commonly tested. The studied subjects were mostly rats (n = 59) and mice (n = 43). The majority of the articles used healthy, wild-type, naïve and non-stressed subjects (n = 71) and 41 articles used stress models (e.g., single prolonged stress). Male subjects were used most (n = 84) whereas only 10 articles used both sexes and 8 articles used females as study subjects. One of the 105 articles used a pretest for the selection of the study subjects. A summary of the descriptive statistics can be found in Tables 6 and 7.
Meta-analysis
Meta-analysis showed that SSRIs significantly reduced anxiety-like behaviour in the elevated plus maze test (effect size (95% CI) 0.47 (0.67, 0.27); p < 0.001)(Fig. 3). Significant within-study and between-study heterogeneity was observed as indicated by significant within and between-study variance, σ2w 0.15 (0.05, 0.28) and σ2b 0.71 (0.46, 1.09), respectively. The planned moderator analyses that we performed to identify sources of heterogeneity suggested that the effect of SSRIs on anxiety-like behaviour is dependent on the disease state of the animals. SSRIs had a significantly larger anxiolytic effect in stressed subjects than in healthy, wild-type, naïve and non-stressed subjects (Supplementary file S4).
Marble burying
Descriptive statistics
The effects of SSRIs on marble burying were tested in 189 unique experiments (63 articles). Of these 63 articles, the majority used fluoxetine (n = 37). The other SSRIs had lower coverage (Table 6) and in most cases, SSRIs were administered acutely (n = 55). In all articles, mice were studied (n = 63) and the majority of these articles used healthy, wild-type, naïve and non-stressed mice (n = 60). In addition, most articles used male study subjects (n = 54) and only 3 articles used female subjects. All descriptive statistics of these experiments can be found in Tables 6 and 7.
Meta-analysis
Meta-analysis could be performed on 179 experiments. Results indicated that SSRIs significantly reduced anxiety-like behaviour in the marble burying test, with an effect size (95% CI) of -1.80 (-2.02, -1.57), p < 0.001 (Fig. 4). Significant between-study heterogeneity was observed as indicated by significant between-study variance, σ2b 0.22 (0.00, 0.62), but no significant within-study heterogeneity was detected, σ2w 1.05 (0.71, 1.52). Moderator analysis indicated that the human equivalent dose (HED) moderated the effect of SSRIs on anxiety-like behaviour. Significantly larger anxiolytic effects of SSRIs were observed with an increasing HED (SMD (95% CI) -0.35 (-0.49, -0.21))(Supplementary file S4).
Ultrasonic vocalization
Descriptive statistics
The effects of SSRIs on ultrasonic vocalization were tested in 52 unique experiments (11 articles). Fluoxetine (n = 7), paroxetine (n = 3), citalopram (n = 2), escitalopram (n = 1) and fluvoxamine (n = 1) were studied and administered acutely (n = 10) in most articles. The studied subjects of 10 articles were rats and 1 article used mice as study subjects. Most of these articles used healthy, wild-type, naïve and non-stressed subjects (n = 11) and 1 article used study subjects that overexpressed corticotropin-releasing factor (CRF). Five articles used both sexes as study subjects, 2 articles used male study subjects and 1 article used female study subjects. Separation-induced ultrasonic vocalization was measured in 8 articles and physical stress-induced ultrasonic vocalization was assessed in 3 articles. A summary of the descriptive statistics can be found in Tables 6 and 7.
Meta-analysis
Meta-analysis showed that SSRIs significantly reduced anxiety-like behaviour in the ultrasonic vocalization test (effect size (95% CI) -1.04 (-1.49, -0.58); p < 0.001)(Fig. 5). Within-study heterogeneity was detected, indicated by significant within-study variance, σ2w 0.12 (0.00, 0.36), but no between-study heterogeneity was observed, σ2b 0.43 (0.12, 1.86). The moderator analysis did not identify any predictors for the SSRI effect in the ultrasonic vocalization test (Supplementary file S4).
Stress-induced hyperthermia
Descriptive statistics
The effect of SSRIs on stress-induced hyperthermia was reported in 15 unique experiments (7 articles). Fluoxetine (n = 3), paroxetine (n = 2), escitalopram (n = 1) and fluvoxamine (n = 1) were studied. SSRIs were administered acutely (n = 6) in most of the articles. The studied subjects were mice (n = 6) and rats (n = 1). All 7 articles used healthy male study subjects, the stressor of the test was either rectal temperature measurement or open-field exposure. Five articles reported on an individual stress-induced hyperthermia test and 2 articles reported a group-housed stress-induced hyperthermia test. All descriptive statistics of these experiments are also shown in Tables 6 and 7.
Meta-analysis
Meta-analysis was performed on six articles and suggested that there was no significant effect of SSRIs on the anxiety response measured in the stress-induced hyperthermia test (effect size (95% CI) -0.68 (-1.44, 0.08); p = 0.08)(Fig. 6). Within-study heterogeneity was present, indicated by significant within-study variance, σ2w 0.00 (0.00, 0.32), but no between-study heterogeneity was observed, σ2b 0.73 (0.16, 4.07). Relevant predictors for the SSRI effect in the stress-induced hyperthermia test were not identified in the moderator analysis (Supplementary file S4).
Locomotor activity
The effect of SSRIs on locomotor activity was reported in 114 experiments of the elevated plus maze dataset, 131 of the experiments of the marble burying dataset, and 11 of the experiments of the ultrasonic vocalization dataset. The majority of these experiments reported no significant effect of SSRIs on locomotor activity (elevated plus maze: n = 96 out of 114, marble burying: n = 117 out of 131, and ultrasonic vocalization: n = 9 out of 11). Many of the studies did not investigate the effect of SSRIs on locomotor activity at all (elevated plus maze: n = 75 out of 189, marble burying: n = 110 out of 231, and ultrasonic vocalization: n = 41 out of 52). All extracted locomotor activity data can be found in Supplementary file S5.
Risk of bias assessment
For all four anxiety tests the risk of bias categories were poorly reported in the respective articles, therefore the risk of bias was mostly scored as unclear. Below, we describe further details regarding the risk of bias assessment for each anxiety test separately (Fig. 7). The complete risk of bias assessment can be found in Supplementary file S2.
Elevated plus maze
In 59% of the articles, it was not mentioned whether the experiment was randomised and 70% of the articles did not mention whether the experiment was blinded. Furthermore, 24% of the articles showed selective outcome reporting. For example, they mentioned outcome measures in the method section which were not reported in the result section. On the other hand, groups were similar at baseline or adjusted for confounders in 68% of the articles and 53% of the articles stated that they were free of conflict of interest (Fig. 7A).
Marble burying
94% of the included articles did not mention whether the experiment was randomized and 81% of the articles did not mention whether the experiment was performed blinded. However, 71% of the articles used experimental groups that were similar at baseline or adjusted for confounders (Fig. 7B).
Ultrasonic vocalizations
64% of the articles did not mention randomization of the experiment and 91% of the articles did not mention whether the experiment was blinded. Also, 18% of the articles exhibited selective outcome reporting. On the other hand, all articles automated the outcome assessment by using video cameras and recording software, leading to a low risk of bias in terms of adequately blinding the outcome assessment (Fig. 7C).
Stress-induced hyperthermia
In 57% of the articles, it was mentioned that the experiment was randomized. However, 71% of the articles did not mention if the experiment was blinded. Groups were similar at baseline or were adjusted for confounders in 71% of the articles. In 57% of the articles, the incomplete outcome data was adequately addressed. A conflict of interest was reported by the authors in 29% of the articles (Fig. 7D).
Publication bias
Visual inspection of the funnel plots of the four unconditioned anxiety tests showed asymmetrical shapes and thus suggested the presence of publication bias in all four datasets (Fig. 8). The asymmetry of the funnel plots was confirmed by the Egger’s test. Results of this test indicated that publication bias was likely for all 4 data sets (elevated plus maze (Z = -8.54, p < 0.01), marble burying (Z = -14.95, p < 0.01), ultrasonic vocalization (Z = -7.11, p < 0.01), and stress-induced hyperthermia test (Z = -4.84, p < 0.01)). The likelihood ratio test indicated that for the marble burying (LRT(2) = 6.72, p < 0.01) and ultrasonic vocalization (LRT(2) = 6.80, p < 0.01) datasets papers with a p-value smaller than 0.05 were more likely to be published, whereas no evidence for such publication bias was found for the elevated plus maze (LRT(2) = 0.72, p = 0.40) and the stress-induced hyperthermia (LRT(2) = 1.15, p = 0.28) datasets.
Discussion
With this review, we aimed to determine the effects of SSRIs on different aspects of unconditioned anxiety. For this, we analysed data from four animal tests for anxiety. Our meta-analysis indicated that SSRIs may reduce avoidance behaviour, burying behaviour and ultrasonic distress vocalizations. We found no evidence of an effect of SSRIs on stress-induced autonomic responses, which might be due to a lack of power. Moderator analysis showed that the effects of SSRIs on approach-avoidance behaviour were more pronounced in stressed animals than in control animals. In addition, the effect of SSRIs on burying behaviour was dose-dependent, with stronger beneficial effects observed with higher dosages. No moderating effect was observed for the type of SSRI, duration of treatment, species, sex, nor use of pre-test. Also, SSRIs do not seem to affect locomotor activity and thus the observed anxiolytic effect of SSRIs is not caused by non-specific effects.
Critical evaluation of the analysed data
To properly evaluate and interpret the results of a meta-analysis, it is important to first assess the quality of the gathered data. The risk of bias and publication bias assessment revealed two major quality issues for all four analysed datasets. First, reporting of preventive measures to reduce the risk of bias was poor in most of the included articles. In many of the articles, it was not mentioned whether the experiments were randomized or blinded. Furthermore, details regarding the allocation sequence generation and concealment were not reported in the majority of the articles. Since for most articles it was unclear whether the preventive measures were not reported or not performed at all, we did not exclude any articles based on their risk of bias assessment. However, this choice could have considerable consequences for the interpretation of the generated results. As in human studies (Saltaji et al. 2018; Schulz et al. 1995), lack of randomization, blinding and allocation concealment may result in overestimation of the effect size in experimental animal studies as well. An analysis of multiple systematic reviews of animal studies found that the failure to randomize, perform a blind outcome assessment and conceal allocation, significantly increased the effect sizes in animal studies (Hirst et al. 2014). Therefore, the lack of transparency in the majority of the analysed articles regarding bias-reducing preventive measures is a reason to interpret the results with caution. Second, there was evidence of publication bias in all four datasets, as indicated by asymmetrical funnel plots and significant Egger’s regression tests. The funnel plot asymmetry could be caused by the overrepresentation of smaller, imprecise studies that favour treatment with SSRIs. This indication of publication bias suggests that the overall effects of SSRIs in our meta-analyses are most likely overestimated and thus emphasizes the importance of interpreting the results with caution. While systematic reviews are of great importance to create an objective overview of the published literature within a specific field of research, if that literature is biased, the results will be biased too. It would be of great value if researchers published their non-significant findings on SSRIs as well. Allowing us to better estimate the unbiased effect of these drugs on anxiety-related behaviour in the future. This emphasizes the advantage of the publication bias assessment within a systematic review compared to a narrative review and its importance, since it will give an estimation of how complete the analysed dataset is and thus indicates to what extent reliable conclusions can be drawn from the published literature. Thus, due to a lack of transparency regarding bias-preventing measures and the reasonable likelihood of publication bias within our systematic review, the results should be interpreted with considerable caution.
It is also important to be aware of the drawbacks of the unconditioned anxiety tests we studied. The elevated plus maze is the most commonly used animal anxiety test. As a result, multiple adaptions of the test exist, leading to inconsistent results and limited comparability due to high variability in methodologies between laboratories (Rodgers and Dalvi 1997). The marble burying test is often used to assess anxiety- and compulsive-like behaviour and to measure the anxiolytic and/or anti-compulsive effect of potential drugs in preclinical testing. However, the translational usefulness is questioned since the results of marble burying testing have been inconsistent and contradictory up to now (de Brouwer et al. 2019). To improve the translational value of the marble burying test it is, for example, suggested to make use of the two-zone configuration where marbles are only placed in one section of the arena. This two-zone paradigm allows for discrimination between anxiety-like and compulsive-like behaviour in this test since animals expressing compulsive-like behaviour should keep demonstrating repetitive burying behaviour even though there is a possibility to avoid this activity (de Brouwer et al. 2019). A drawback of the separation-induced ultrasonic vocalization test in infantile rodents is that the brains of these animals are not yet fully developed at this stage (Semple et al. 2013). Also, many factors can influence the number of USVs that are emitted by the infant rodents such as the temperature of the test environment, the state of satiation, or the presence of the mother or littermates in the recording area (Hofer and Shair 1978; Hofer and Shair 1992; Nelson and Alberts 2002). In addition, all three aforementioned anxiety tests involve locomotor activity. Readouts of elevated plus maze and marble burying tests are directly related to locomotor activity whereas ultrasonic vocalizations may be indirectly correlated with locomotor activity (Laplagne and Elias Costa 2016; Schwarting et al. 2007). When testing pharmacological agents in these tests, their sedative and motor effects should always be investigated to ensure that the effect measured is specific to anxiety and not due to side effects of the agent. In our dataset, 47% of the elevated plus maze studies, 69% of the marble burying studies, and 21% of the ultrasonic vocalization studies also tested the effect of SSRIs on motor activity (Supplementary file S5). A drawback of the stress-induced hyperthermia test is that the hyperthermic response observed in animals is the opposite of the decreased intestinal temperature observed in stressed healthy humans (Vinkers et al. 2013). Since stress leads to consistent body temperature changes in humans, body temperature is still considered a good physiological outcome measure of stress. As suggested by (Vinkers et al. 2013), the use of the stress-induced hyperthermia test could potentially provide early proof of concept of drug effectiveness and thus aid the development of anxiolytic drugs. Lastly, all four tests may detect anxiolytic drug effects upon acute drug administration. Acute beneficial treatment effects of SSRIs, however, do not resemble the clinical situation and could be considered a drawback of these tests (Lenze et al. 2005; Rickels et al. 2003). Testing drug effects in animals with a pre-existing anxiety condition could mimic the clinical situation and associated drug exposure effects more accurately. Our meta-analyses, however, did not detect moderator effects for ‘disease induction’ (except for the elevated plus maze) and ‘duration of treatment’. This is likely due to limited data availability, but may also suggest that these tests have limited predictive validity with regard to duration of treatment exposure.
Effect of SSRIs on unconditioned anxiety
Bayesian regularized meta-regression suggested that based on the available data, SSRIs may reduce multiple unconditioned anxiety aspects in animals. Three of the investigated unconditioned anxiety tests show sensitivity to the anxiolytic effect of SSRIs, the implications of these results will be discussed here. Our study suggests that SSRIs may reduce avoidance behaviour in animals. Avoidance behaviour as observed in the elevated plus maze can be linked to the extensive avoidance of feared objects or situations which is typical for individuals with an anxiety-like disorder. In addition, the conflict between approaching and avoiding the open areas in the elevated plus maze is a familiar concept of opposite drives as seen in the psychodynamic theories of human anxiety. Our results also suggested that repetitive burying behaviour in animals might be reduced after SSRI treatment. This repetitive behaviour in rodents resembles the increased stereotype pattern behaviour seen in obsessive-compulsive disorder (OCD) patients. Furthermore, our meta-analysis suggests that SSRIs may reduce the ultrasonic distress vocalizations in animals. The 22-kHz and the 40-kHz ultrasonic vocalizations in rats and mice, respectively, are used to communicate a negative emotional state and are induced when the animal is subjected to aversive conditions (Brudzynski 2007; Litvin et al. 2007). These ultrasonic distress vocalizations thus represent the distress that is experienced when exposed to unavoidable aversive situations (Jelen et al. 2003), which is often experienced by patients with anxiety.
Together, this meta-analysis, and our previous meta-analysis that investigated the effect of SSRIs on conditioned fear (Heesbeen et al. 2023) suggest that SSRIs might reduce many anxiety aspects in animals. Clinical data demonstrates that SSRIs are effective in treating various anxiety-like disorders. This raises the question of whether the anxiolytic effect of SSRIs that is observed in animals and humans is selective for specific anxiety aspects or whether it results from a general inhibition of fear-related emotions. Emotional blunting is frequently observed in patients who are chronically treated with SSRIs. Patients who experience emotional blunting are not able to express their feelings, both verbally and non-verbally, particularly when discussing issues that would normally require some emotional engagement (Opbroek et al. 2002; Reinblatt and Riddle 2006; Sansone and Sansone 2010). Even though they experience less emotional pain than before the treatment, other emotions that are a part of everyday life are also experienced to a lesser extent (Price et al. 2009). Emotional blunting as a result of SSRI treatment has not been investigated in anxiety patients yet. Based on our results it could be interesting to investigate to what extent general inhibition of fear-related emotions is responsible for the anxiolytic effect of SSRIs in animals and humans.
A moderator analysis was performed to assess the impact of a predefined list of study characteristics on the overall heterogeneity found within these unconditioned anxiety tests. The effect of SSRIs seemed to be moderated by pre-existing anxiety conditions in the elevated plus maze and dose dependency in the marble burying test. Theoretically, these conditions are expected to moderate the beneficial effect of SSRIs in all tests but were only identified as moderators of the SSRI effect in these two tests. Also, the current meta-analysis found no evidence that one of the other predefined moderators (type of SSRI, duration of treatment, species, sex, and use of pretest) influenced the pooled effect in any of the four unconditioned anxiety tests. The absence of a moderating effect of the type of SSRI is not surprising considering that all six SSRIs are used to treat anxiety-like disorders such as generalized anxiety disorder, social anxiety disorder and obsessive-compulsive disorder albeit according to clinical guidelines or as off-label use (Sartori and Singewald 2019). However, the lack of a moderating effect of duration of treatment was not expected since SSRIs have a delayed onset of action in the clinical treatment of anxiety-like disorders (Lenze et al. 2005; Rickels et al. 2003). Interestingly, duration of treatment does moderate the effect of SSRIs on cued fear expression as shown in our previous systematic review (Heesbeen et al. 2023). This may suggest that the anxiolytic effect of SSRIs is achieved differently in conditioned and unconditioned anxiety. Given the limited availability of data on many of the moderators, the absence of moderating effects in the current analysis should be interpreted with caution. For example, the absence of a dose-dependent effect in three of the included tests can be explained by the experimental setups that were used in these three unconditioned anxiety tests. It may well be that the dose-dependent effect found for the marble burying test would have been observed in the other three tests if a higher number of dose-response experiments were performed. Thus, due to insufficient availability of data, the current moderator analysis does not allow us to gain more insight into which conditions or circumstances influence the effect of SSRIs on unconditioned anxiety.
Future research
The main goal of our systematic review was to investigate the effect of SSRIs on multiple unconditioned anxiety aspects. Due to the low quality of the included studies, no reliable conclusions can be drawn concerning this. Therefore we want to emphasize that the main takeaway of this systematic review is that the quality of (animal) research should be improved by promoting and enforcing transparency regarding bias-reducing measures (e.g. blinding, randomization, and allocation sequencing). In addition, it should always be reported how many animals were used per experimental group and missing data points should always be adequately addressed. Also, the publication of all results regardless of significance should be encouraged to ensure a complete and unbiased body of evidence. The latter can be stimulated by implementing preregistration of (animal) studies which aids the design of proper research studies and promotes the reporting of all outcomes (Heinl et al. 2022). In addition, scientific journals could facilitate the publication of non-significant findings more. When these changes are implemented, we will be more confident that the results of future systematic reviews will reflect the population effect more accurately and thus more reliable conclusions can be drawn regarding the anxiolytic effect of SSRIs.
Additionally, increasing the quality of the execution and reporting of animal studies could aid the identification of new therapeutic targets for patients with anxiety-like disorders. If all studies were executed properly and reported regardless of significance there might have been tests of unconditioned anxiety that clearly did not show an anxiolytic effect of SSRIs. These tests could reflect the SSRI non-responder group and could be interesting to investigate potential anxiolytics for this patient group. Similarly, it could be reliably determined which tests of unconditioned anxiety are sensitive to the anxiolytic effect of SSRIs. These tests could be used to identify new pharmacological treatments that, for example, show an acute anxiolytic response in these SSRI-sensitive behavioural tests.
Knowledge gaps
First, the majority of the studied subjects in all four tests were male whereas females were only studied in a minority of the experiments. In humans however, women are more likely to develop anxiety disorder than men (Angst and Dobler-Mikola 1985; Bruce et al. 2005; Regier et al. 1990), and there is preliminary evidence that women respond differently to antidepressants such as SSRIs (Khan et al. 2005; Yang et al. 2011). The translational value of these animal studies would thus be improved by carrying out further experiments on female subjects. Second, fluoxetine was by far the most studied SSRI whereas the other SSRIs were only studied in a few articles. Therefore, the potential differences in efficacy between the six SSRIs could not be investigated properly in this systematic review. Third, only a few articles investigated the effect of SSRIs on stress-induced hyperthermia. Compared to the other unconditioned anxiety tests, the stress-induced hyperthermia test measures the autonomic response to stress instead of a behavioural response. No effect of SSRIs on stress-induced hyperthermia was observed. This suggests that SSRIs might not affect the autonomic stress response but only on behavioural responses to stress. However, very few studies investigated the effect of SSRIs on stress-induced hyperthermia and publication bias was present. Therefore more research is needed to investigate the effect of SSRIs on the autonomic stress response.
Limitations of the systematic review design
The results of this systematic review should be interpreted in light of the protocol’s limitations. First, during the full-text assessment, articles that performed other behavioural tests before the anxiety test of interest were excluded since the performance of animals can be dependent on the order of a test battery (Blokland et al. 2012). Order of reporting was used to determine the test order when a timeline was not available. This could have resulted in the inclusion of animals previously exposed to behavioural tests but also in the exclusion of animals that were naïve to behavioural testing. This uncertainty needs to be taken into account when interpreting the results. However, it is difficult to predict to what extent this occurred since we are not able to determine how many cases this concerns. Furthermore, the selection based on test order could have also contributed to the observed publication bias. Including studies in which the main focus was the effect of SSRIs on unconditioned anxiety will most likely increase the observed publication bias whereas studies that investigated the anxiolytic effect of SSRIs as a secondary focus will probably demonstrate less publication bias. The second limitation relates to the many different outcome measures of the elevated plus maze that were reported, we predefined a limited number of outcome parameters to reduce heterogeneity and prevent dependency within the dataset. This approach of outcome selection might have altered the overall effect and/or moderator effects. A third limitation pertains to the choice of study characteristics included in the moderator analysis. Some of the extracted study characteristics such as age of the animals and route of administration of the SSRI were not investigated. To reliably examine heterogeneity a relatively high number of experiments is needed per moderator. Since the investigated dataset was relatively small compared to the number of potentially relevant moderators, a selection of moderators was made that were deemed to be most relevant based on previous research (Riley et al. 2011). Thus, part of the remaining heterogeneity might have been explained by including additional study characteristics in the moderator analysis.
Conclusion
On average, the published literature shows an anxiolytic effect of SSRIs on unconditioned anxiety aspects. These results combined with our previous systematic review on the effects of SSRIs on conditioned anxiety suggest a more general blunting of emotions by SSRIs. The contribution of emotional blunting to the anxiolytic effect of SSRIs should be investigated further. However, these results should be interpreted with substantial caution since the quality of evidence was low. Bias-reducing preventive measures were not reported in the majority of studies. We, therefore, recommend improving the quality of reporting and the conduct of research in animal studies to avoid bias from taking place. Furthermore, publication bias was present for all four unconditioned anxiety tests, suggesting that our analysed dataset was incomplete and thus preventing us from drawing reliable conclusions. To obtain an unbiased estimate of the potential effects of SSRIs, researchers ought to publish all relevant studies, regardless of significance. Preregistration and registered reports may help achieve this goal. Our systematic review demonstrates that even though a lot of research has been performed within this field using many laboratory animals, we are still very limited in drawing any conclusions on how SSRIs affect anxiety. Future research should thus focus on improving the design and the execution of animal studies, thereby enhancing their reliability. On the other hand, since the use of animal studies has thus far not provided conclusive results, the use of human studies could also be considered as a possible valuable alternative to the currently used animal studies.
References
Abd El Wahab MG, Ali SS, Ayuob NN (2018) The Role of Musk in relieving the neurodegenerative changes induced after exposure to chronic stress. Am J Alzheimers Dis Other Demen 33: 221–231.
Abe M, Nakai H, Tabata R, Saito K, Egawa M (1998) Effect of 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a novel 5-HT1A-receptor agonist, on aggressive behavior and marble burying behavior in mice. Jpn J Pharmacol 76: 297–304.
Afzal M, Kazmi I, Quazi AM, Khan SA, Zafar A, Al-Abbasi FA, Imam F, Alharbi KS, Alzarea SI, Yadav N (2022) 6-Shogaol Attenuates Traumatic Brain Injury-Induced Anxiety/Depression-like Behavior via Inhibition of Oxidative Stress-Influenced Expressions of Inflammatory Mediators TNF-alpha, IL-1beta, and BDNF: Insight into the Mechanism. ACS Omega 7: 140–148.
Aguilar-Martinez IS, Reyes-Mendez ME, Herrera-Zamora JM, Osuna-Lopez F, Virgen-Ortiz A, Mendoza-Munoz N, Gongora-Alfaro JL, Moreno-Galindo EG, Alamilla J (2020) Synergistic antidepressant-like effect of capsaicin and citalopram reduces the side effects of citalopram on anxiety and working memory in rats. Psychopharmacology (Berl) 237: 2173–2185.
Ahmed K, Dubey BK, Shrivastava B, Sharma PK, Nadeem S (2015) Anxiolytic effects of newly synthesized derivatives in mice and molecular docking studies as serotonin 5HT2A receptor inhibitor
Ali SS, Abd El Wahab MG, Ayuob NN, Suliaman M (2017) The antidepressant-like effect of Ocimum basilicum in an animal model of depression. Biotech Histochem 92: 390–401.
Angst J, Dobler-Mikola A (1985) The Zurich Study. V. Anxiety and phobia in young adults. Eur Arch Psychiatry Neurol Sci 235: 171-8.
Anwar MJ, Pillai KK, Samad A, Vohora D (2013) Effect of escitalopram on cardiomyopathy-induced anxiety in mice. Hum Exp Toxicol 32: 632-9.
Ariel L, Inbar S, Edut S, Richter-Levin G (2017) Fluoxetine treatment is effective in a rat model of childhood-induced post-traumatic stress disorder. Transl Psychiatry 7: 1260.
Aykac A, Aydin B, Cabadak H, Goren MZ (2012) The change in muscarinic receptor subtypes in different brain regions of rats treated with fluoxetine or propranolol in a model of post-traumatic stress disorder. Behav Brain Res 232: 124-9.
Aykaç A, Gören MZ, Cabadak H (2015) Altered ratio of proapoptotic and antiapoptotic proteins in different brain regions of female rats in model of post-traumatic stress disorder / [Post-travmatik stres hastalığı modelinde dişi sıçanların farklı beyin bölgelerinde proapoptotik ve antiapoptotik proteinlerin oranındaki değişim]. 40: 1–7.
Ayuob NN, Ali SS, Abd El Wahab MG (2018a) Can ocimum basilicum (basil) relief the impact of chronic unpredictable mild stress on the mice salivary glands? African Journal of Traditional, Complementary and Alternative Medicines 15: 1–11.
Ayuob NN, El Wahab MGA, Ali SS, Abdel-Tawab HS (2018b) Ocimum basilicum improve chronic stress-induced neurodegenerative changes in mice hippocampus. Metab Brain Dis 33: 795–804.
Ayuob NN, Firgany AEL, El-Mansy AA, Ali S (2017) Can Ocimum basilicum relieve chronic unpredictable mild stress-induced depression in mice? Exp Mol Pathol 103: 153–161.
Azevedo H, Ferreira M, Costa RW, Russo V, Russo E, Mascarello A, Guimaraes CRW (2019) Preclinical characterization of ACH-000029, a novel anxiolytic compound acting on serotonergic and alpha-adrenergic receptors. Prog Neuropsychopharmacol Biol Psychiatry 95: 109707.
Bespalov AY, van Gaalen MM, Sukhotina IA, Wicke K, Mezler M, Schoemaker H, Gross G (2008) Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression. Eur J Pharmacol 592: 96–102.
Bhatt S, Mahesh R, Devadoss T, Jindal A (2017) Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6 g) on lipopolysaccharide-induced anxiety models in mice. J Basic Clin Physiol Pharmacol 28: 101–106.
Blokland A, Ten Oever S, van Gorp D, van Draanen M, Schmidt T, Nguyen E, Krugliak A, Napoletano A, Keuter S, Klinkenberg I (2012) The use of a test battery assessing affective behavior in rats: order effects. Behav Brain Res 228: 16–21.
Bregin A, Kaare M, Jagomae T, Karis K, Singh K, Laugus K, Innos J, Leidmaa E, Heinla I, Visnapuu T, Oja EM, Koiv K, Lillevali K, Harro J, Philips MA, Vasar E (2020) Expression and impact of Lsamp neural adhesion molecule in the serotonergic neurotransmission system. Pharmacol Biochem Behav 198: 173017.
Brown HD, Amodeo DA, Sweeney JA, Ragozzino ME (2012) The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning. J Psychopharmacol 26: 1443-55.
Bruce SE, Yonkers KA, Otto MW, Eisen JL, Weisberg RB, Pagano M, Shea MT, Keller MB (2005) Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study. Am J Psychiatry 162: 1179-87.
Brudzynski SM (2007) Ultrasonic calls of rats as indicator variables of negative or positive states: acetylcholine-dopamine interaction and acoustic coding. Behav Brain Res 182: 261 − 73.
Bruins Slot LA, Bardin L, Auclair AL, Depoortere R, Newman-Tancredi A (2008) Effects of antipsychotics and reference monoaminergic ligands on marble burying behavior in mice. Behav Pharmacol 19: 145 − 52.
Bui E, Orr SP, Jacoby RJ, Keshaviah A, LeBlanc NJ, Milad MR, Pollack MH, Simon NM (2013) Two weeks of pretreatment with escitalopram facilitates extinction learning in healthy individuals. Hum Psychopharmacol 28: 447 − 56.
Campos AC, Ferreira FR, Guimaraes FS (2012) Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. J Psychiatr Res 46: 1501-10.
Casarotto PC, Gomes FV, Resstel LB, Guimaraes FS (2010) Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav Pharmacol 21: 353-8.
Chaki S, Hirota S, Funakoshi T, Suzuki Y, Suetake S, Okubo T, Ishii T, Nakazato A, Okuyama S (2003) Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor. J Pharmacol Exp Ther 304: 818 − 26.
Chanchal R, Balasubramaniam A, Navin R, Nadeem S (2015) Tabernaemontana divaricata leaves extract exacerbate burying behavior in mice. Avicenna J Phytomed 5: 282-7.
Cohen H, Zohar J, Kaplan Z, Arnt J (2018) Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms. Eur Neuropsychopharmacol 28: 63–74.
Coleman RB, Aguirre K, Spiegel HP, Pecos C, Carr JA, Harris BN (2019) The plus maze and scototaxis test are not valid behavioral assays for anxiety assessment in the South African clawed frog. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 205: 567–582.
Collins HM, Pinacho R, Ozdemir D, Bannerman DM, Sharp T (2022) Effect of selective serotonin reuptake inhibitor discontinuation on anxiety-like behaviours in mice. J Psychopharmacol 36: 794–805.
Cuomo V, Cagiano R, De Salvia MA, Maselli MA, Renna G, Racagni G (1988) Ultrasonic vocalization in response to unavoidable aversive stimuli in rats: effects of benzodiazepines. Life Sci 43: 485 − 91.
Dankoski EC, Agster KL, Fox ME, Moy SS, Wightman RM (2014) Facilitation of serotonin signaling by SSRIs is attenuated by social isolation. Neuropsychopharmacology 39: 2928-37.
Dawson LA, Hughes ZA, Starr KR, Storey JD, Bettelini L, Bacchi F, Arban R, Poffe A, Melotto S, Hagan JJ, Price GW (2006) Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): in vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity. Neuropharmacology 50: 975 − 83.
de Brouwer G, Fick A, Harvey BH, Wolmarans W (2019) A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive-compulsive disorder: Mapping the way forward. Cogn Affect Behav Neurosci 19: 1–39.
de Vries RB, Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M (2014) Updated version of the Embase search filter for animal studies. Lab Anim 48: 88.
De Boer SF, Koolhaas JM (2003) Defensive burying in rodents: ethology, neurobiology and psychopharmacology. Eur J Pharmacol 463: 145 − 61.
Dixit PV, Parihar G, Jain DK, Jaiswal P (2012) Increased serotonergic neurotransmission is not responsible for the anticompulsive effect of berberine in a murine model of obsessive-compulsive disorder. Behav Pharmacol 23: 716 − 21.
Doron R, Lotan D, Versano Z, Benatav L, Franko M, Armoza S, Kately N, Rehavi M (2014) Escitalopram or novel herbal mixture treatments during or following exposure to stress reduce anxiety-like behavior through corticosterone and BDNF modifications. PLoS One 9: e91455.
Drapier D, Bentue-Ferrer D, Laviolle B, Millet B, Allain H, Bourin M, Reymann JM (2007) Effects of acute fluoxetine, paroxetine and desipramine on rats tested on the elevated plus-maze. Behav Brain Res 176: 202-9.
Durand M, Aguerre S, Fernandez F, Edno L, Combourieu I, Mormede P, Chaouloff F (2000) Strain-dependent neurochemical and neuroendocrine effects of desipramine, but not fluoxetine or imipramine, in spontaneously hypertensive and Wistar-Kyoto rats. Neuropharmacology 39: 2464-77.
Dygalo NN, Shishkina GT, Kalinina TS, Yudina AM, Ovchinnikova ES (2006) Effect of repeated treatment with fluoxetine on tryptophan hydroxylase-2 gene expression in the rat brainstem. Pharmacol Biochem Behav 85: 220-7.
Egashira N, Harada S, Okuno R, Matsushita M, Nishimura R, Mishima K, Iwasaki K, Orito K, Fujiwara M (2007) Involvement of the sigma1 receptor in inhibiting activity of fluvoxamine on marble-burying behavior: comparison with paroxetine. Eur J Pharmacol 563: 149 − 54.
Egashira N, Kubota N, Goto Y, Watanabe T, Kubota K, Katsurabayashi S, Iwasaki K (2018) The antipsychotic trifluoperazine reduces marble-burying behavior in mice via D(2) and 5-HT(2A) receptors: Implications for obsessive-compulsive disorder. Pharmacol Biochem Behav 165: 9–13.
Egashira N, Okuno R, Shirakawa A, Nagao M, Mishima K, Iwasaki K, Oishi R, Fujiwara M (2012a) Role of 5-hydroxytryptamine2C receptors in marble-burying behavior in mice. Biol Pharm Bull 35: 376-9.
Egashira N, Shirakawa A, Abe M, Niki T, Mishima K, Iwasaki K, Oishi R, Fujiwara M (2012b) N-acetyl-L-cysteine inhibits marble-burying behavior in mice. J Pharmacol Sci 119: 97–101.
Farley S, Apazoglou K, Witkin JM, Giros B, Tzavara ET (2010) Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int J Neuropsychopharmacol 13: 1207-18.
Gannon RL, Lungwitz E, Batista N, Hester I, Huntley C, Peacock A, Delagrange P, Millan MJ (2011) The benzodiazepine diazepam demonstrates the usefulness of Syrian hamsters as a model for anxiety testing: evaluation of other classes of anxiolytics in comparison to diazepam. Behav Brain Res 218: 8–14.
Gardner CR (1985) Distress vocalization in rat pups. A simple screening method for anxiolytic drugs. J Pharmacol Methods 14: 181-7.
Garg R, Kumar A (2008) Possible role of citalopram and desipramine against sleep deprivation-induced anxiety like-behavior alterations and oxidative damage in mice. Indian J Exp Biol 46: 770-6.
Gergues MM, Yohn CN, Bharadia A, Levinstein MR, Samuels BA (2021) Dentate gyrus activin signaling mediates the antidepressant response. Transl Psychiatry 11: 7.
Girdhar S, Wanjari MM, Prajapati SK, Girdhar A (2010) Evaluation of anti-compulsive effect of methanolic extract of Benincasa hispida Cogn. fruit in mice. Acta Pol Pharm 67: 417 − 21.
Gobert A, Brocco M, Dekeyne A, Di Cara B, Bouchez G, Lejeune F, Gannon RL, Millan MJ (2009) Neurokinin1 antagonists potentiate antidepressant properties of serotonin reuptake inhibitors, yet blunt their anxiogenic actions: a neurochemical, electrophysiological, and behavioral characterization. Neuropsychopharmacology 34: 1039-56.
Gomez F, Garcia-Garcia L (2017) Anxiogenic-like effects of fluoxetine render adult male rats vulnerable to the effects of a novel stress. Pharmacol Biochem Behav 153: 32–44.
Grassi G, Micheli L, Di Cesare Mannelli L, Compagno E, Righi L, Ghelardini C, Pallanti S (2016) Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation. J Psychiatr Res 83: 240–248.
Gregoire S, Neugebauer V (2013) 5-HT2CR blockade in the amygdala conveys analgesic efficacy to SSRIs in a rat model of arthritis pain. Mol Pain 9: 41.
Griebel G, Rodgers RJ, Perrault G, Sanger DJ (1997) Risk assessment behaviour: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test. Pharmacol Biochem Behav 57: 817 − 27.
Grundmann O, Kelber O, Butterweck V (2006) Effects of St. John’s wort extract and single constituents on stress-induced hyperthermia in mice. Planta Med 72: 1366-71.
Guo F, Yan D, Qin Z, Bais S (2021) Prunin modulates the Expression of Cerebral Serotonin Induced by Anxiety-Like Behavior in Mice. Natural Product Communications 16: 1934578X21991664.
Gutierrez-Garcia AG, Contreras CM (2021) Putative Anti-Immobility Action of Acute Insulin Is Attributable to an Increase in Locomotor Activity in Healthy Wistar Rats. Neuropsychobiology 80: 483–492.
Hagsater SM, Pettersson R, Pettersson C, Atanasovski D, Naslund J, Eriksson E (2021) A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear. Int J Neuropsychopharmacol 24: 749–757.
Han SK, Kim DH (2019) Lactobacillus mucosae and Bifidobacterium longum Synergistically Alleviate Immobilization Stress-Induced Anxiety/Depression in Mice by Suppressing Gut Dysbiosis. J Microbiol Biotechnol 29: 1369–1374.
Harasawa T, Ago Y, Itoh S, Baba A, Matsuda T (2006) Role of serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice. Behav Pharmacol 17: 637 − 40.
Hayashi E, Kuratani K, Kinoshita M, Hara H (2010) Pharmacologically distinctive behaviors other than burying marbles during the marble burying test in mice. Pharmacology 86: 293-6.
Heesbeen EJ, Bijlsma EY, Verdouw PM, van Lissa C, Hooijmans C, Groenink L (2023) The effect of SSRIs on fear learning: a systematic review and meta-analysis. Psychopharmacology (Berl) 240: 2335–2359.
Heinl C, Schönfelder G, Bert B (2022) Preregistration in Animal Research. In: Faintuch J, Faintuch S (eds) Integrity of Scientific Research: Fraud, Misconduct and Fake News in the Academic, Medical and Social Environment. Springer International Publishing, Cham, pp 371–378
Hiraide S, Ueno K, Yamaguchi T, Matsumoto M, Yanagawa Y, Yoshioka M, Togashi H (2013) Behavioural effects of monoamine reuptake inhibitors on symptomatic domains in an animal model of attention-deficit/hyperactivity disorder. Pharmacol Biochem Behav 105: 89–97.
Hirano K, Kato Y, Uchida S, Sugimoto Y, Yamada J, Umegaki K, Yamada S (2004) Effects of oral administration of extracts of Hypericum perforatum (St John’s wort) on brain serotonin transporter, serotonin uptake and behaviour in mice. J Pharm Pharmacol 56: 1589-95.
Hirano K, Kimura R, Sugimoto Y, Yamada J, Uchida S, Kato Y, Hashimoto H, Yamada S (2005) Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors. Br J Pharmacol 144: 695–702.
Hirst JA, Howick J, Aronson JK, Roberts N, Perera R, Koshiaris C, Heneghan C (2014) The need for randomization in animal trials: an overview of systematic reviews. PLoS One 9: e98856.
Hodgson RA, Guthrie DH, Varty GB (2008) Duration of ultrasonic vocalizations in the isolated rat pup as a behavioral measure: sensitivity to anxiolytic and antidepressant drugs. Pharmacol Biochem Behav 88: 341-8.
Hofer MA, Shair H (1978) Ultrasonic vocalization during social interaction and isolation in 2-weeek-old rats. Dev Psychobiol 11: 495–504.
Hofer MA, Shair HN (1992) Ultrasonic vocalization by rat pups during recovery from deep hypothermia. Dev Psychobiol 25: 511 − 28.
Holmes A, Rodgers RJ (2003) Prior exposure to the elevated plus-maze sensitizes mice to the acute behavioral effects of fluoxetine and phenelzine. Eur J Pharmacol 459: 221 − 30.
Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14: 43.
Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M (2010) Enhancing search efficiency by means of a search filter for finding all studies on animal experimentation in PubMed. Lab Anim 44: 170-5.
Hughes ZA, Neal SJ, Smith DL, Sukoff Rizzo SJ, Pulicicchio CM, Lotarski S, Lu S, Dwyer JM, Brennan J, Olsen M, Bender CN, Kouranova E, Andree TH, Harrison JE, Whiteside GT, Springer D, O’Neil SV, Leonard SK, Schechter LE, Dunlop J, Rosenzweig-Lipson S, Ring RH (2013) Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Neuropharmacology 66: 202 − 14.
Huot RL, Thrivikraman KV, Meaney MJ, Plotsky PM (2001) Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment. Psychopharmacology (Berl) 158: 366 − 73.
Ichimaru Y, Egawa T, Sawa A (1995) 5-HT1A-receptor subtype mediates the effect of fluvoxamine, a selective serotonin reuptake inhibitor, on marble-burying behavior in mice. Jpn J Pharmacol 68: 65–70.
Iijima M, Chaki S (2005) Separation-induced ultrasonic vocalization in rat pups: further pharmacological characterization. Pharmacol Biochem Behav 82: 652-7.
Ishizuka Y, Abe H, Tanoue A, Kannan H, Ishida Y (2010) Involvement of vasopressin V1b receptor in anti-anxiety action of SSRI and SNRI in mice. Neurosci Res 66: 233-7.
Jacobsen JP, Plenge P, Sachs BD, Pehrson AL, Cajina M, Du Y, Roberts W, Rudder ML, Dalvi P, Robinson TJ, O’Neill SP, Khoo KS, Morillo CS, Zhang X, Caron MG (2014) The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse. Psychopharmacology (Berl) 231: 4527-40.
Jamal M, Rehman MU, Nabi M, Awan AA, Ali N, Sherkheli MA, Haq RU (2019) Evaluation of safety profile and stress suppressant activity of Rosa moschata in mice. Pak J Pharm Sci 32: 2659–2665.
Jelen P, Soltysik S, Zagrodzka J (2003) 22-kHz ultrasonic vocalization in rats as an index of anxiety but not fear: behavioral and pharmacological modulation of affective state. Behav Brain Res 141: 63–72.
Jennings KA, Loder MK, Sheward WJ, Pei Q, Deacon RM, Benson MA, Olverman HJ, Hastie ND, Harmar AJ, Shen S, Sharp T (2006) Increased expression of the 5-HT transporter confers a low-anxiety phenotype linked to decreased 5-HT transmission. J Neurosci 26: 8955-64.
Jo KJ, Nam GH, Park YS, Kawk HW, Kim JT, Choi WH, Jang SH, Kim MJ, Kim YM (2020) Evaluation of Stress-related Behavioral and Biological Activity of Ocimum sanctum Extract in Rats. Biotechnology and Bioprocess Engineering 25: 170–180.
Jury NJ, McCormick BA, Horseman ND, Benoit SC, Gregerson KA (2015) Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation. PLoS One 10: e0117339.
Kalariya M, Prajapati R, Parmar SK, Sheth N (2015) Effect of hydroalcoholic extract of leaves of Colocasia esculenta on marble-burying behavior in mice: Implications for obsessive-compulsive disorder. Pharm Biol 53: 1239-42.
Kalshetty P, Aswar U, Bodhankar S, Sinnathambi A, Mohan V, Thakurdesai P (2012) Antidepressant effects of standardized extract of Centella asiatica L in olfactory bulbectomy model. Biomedicine & Aging Pathology 2: 48–53.
Kaminska K, Rogoz Z (2016) The antidepressant- and anxiolytic-like effects following co-treatment with escitalopram and risperidone in rats. J Physiol Pharmacol 67: 471 − 80.
Kangussu LM, Almeida-Santos AF, Bader M, Alenina N, Fontes MA, Santos RA, Aguiar DC, Campagnole-Santos MJ (2013) Angiotensin-(1–7) attenuates the anxiety and depression-like behaviors in transgenic rats with low brain angiotensinogen. Behav Brain Res 257: 25–30.
Kassai F, Gyertyan I (2012) Shock priming enhances the efficacy of SSRIs in the foot shock-induced ultrasonic vocalization test. Prog Neuropsychopharmacol Biol Psychiatry 36: 128 − 35.
Kaurav BP, Wanjari MM, Chandekar A, Chauhan NS, Upmanyu N (2012) Influence of Withania somnifera on obsessive compulsive disorder in mice. Asian Pac J Trop Med 5: 380-4.
Kaygisiz B, Ozatik FY, Erol K (2014) Interaction of sertraline and nimodipine on some behavioural tests in rats. Adv Clin Exp Med 23: 169 − 75.
Khan A, Brodhead AE, Schwartz KA, Kolts RL, Brown WA (2005) Sex differences in antidepressant response in recent antidepressant clinical trials. J Clin Psychopharmacol 25: 318 − 24.
Kilic FS, Ismailoglu S, Kaygisiz B, Oner S (2014) Effects of single and combined gabapentin use in elevated plus maze and forced swimming tests. Acta Neuropsychiatr 26: 307 − 14.
Kim S, Kim S, Khalid A, Jeong Y, Jeong B, Lee ST, Jung KH, Chu K, Lee SK, Jeon D (2016) Rhythmical Photic Stimulation at Alpha Frequencies Produces Antidepressant-Like Effects in a Mouse Model of Depression. PLoS One 11: e0145374.
Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA, Jr. (2007) Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 323: 838 − 45.
Kobayashi T, Hayashi E, Shimamura M, Kinoshita M, Murphy NP (2008) Neurochemical responses to antidepressants in the prefrontal cortex of mice and their efficacy in preclinical models of anxiety-like and depression-like behavior: a comparative and correlational study. Psychopharmacology (Berl) 197: 567 − 80.
Koks S, Beljajev S, Koovit I, Abramov U, Bourin M, Vasar E (2001) 8-OH-DPAT, but not deramciclane, antagonizes the anxiogenic-like action of paroxetine in an elevated plus-maze. Psychopharmacology (Berl) 153: 365 − 72.
Koks S, Bourin M, Voikar V, Soosaar A, Vasar E (1999) Role of CCK in anti-exploratory action of paroxetine, 5-HT reuptake inhibitor. Int J Neuropsychopharmacol 2: 9–16.
Komatsu H, Furuya Y, Sawada K, Asada T (2015) Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups. Eur J Pharmacol 746: 252-7.
Kothari S, Minda M, Tonpay SD (2010) Anxiolytic and antidepressant activities of methanol extract of Aegle marmelos leaves in mice. Indian J Physiol Pharmacol 54: 318 − 28.
Krass M, Runkorg K, Wegener G, Volke V (2010) Nitric oxide is involved in the regulation of marble-burying behavior. Neurosci Lett 480: 55 − 8.
Kudryashov NV, Kalinina TS, Zhmurenko LA, Voronina TA (2016) Anticompulsive Activity of a New Pyrazolo[C]Pyridine Derivative GIZh-72 under Conditions of Unpredictable Chronic Mild Stress. Bull Exp Biol Med 161: 377 − 80.
Kurt M, Arik AC, Celik S (2000) The effects of sertraline and fluoxetine on anxiety in the elevated plus-maze test in mice. J Basic Clin Physiol Pharmacol 11: 173 − 80.
Laplagne DA, Elias Costa M (2016) Rats Synchronize Locomotion with Ultrasonic Vocalizations at the Subsecond Time Scale. Front Behav Neurosci 10: 184.
Lapmanee S, Charoenphandhu N, Krishnamra N, Charoenphandhu J (2012) Anxiolytic-like actions of reboxetine, venlafaxine and endurance swimming in stressed male rats. Behav Brain Res 231: 20 − 8.
Leao FF, Waltrick APF, Verri WA, Jr., da Cunha JM, Zanoveli JM (2022) Resolvin D5 disrupts anxious- and depressive-like behaviors in a type 1 diabetes mellitus animal model. Naunyn Schmiedebergs Arch Pharmacol 395: 1269–1282.
Lecci A, Borsini F, Volterra G, Meli A (1990) Pharmacological validation of a novel animal model of anticipatory anxiety in mice. Psychopharmacology (Berl) 101: 255 − 61.
Lenze EJ, Mulsant BH, Shear MK, Dew MA, Miller MD, Pollock BG, Houck P, Tracey B, Reynolds CF, 3rd (2005) Efficacy and tolerability of citalopram in the treatment of late-life anxiety disorders: results from an 8-week randomized, placebo-controlled trial. Am J Psychiatry 162: 146 − 50.
Li MM, Jiang ZE, Song LY, Quan ZS, Yu HL (2017) Antidepressant and anxiolytic-like behavioral effects of erucamide, a bioactive fatty acid amide, involving the hypothalamus-pituitary-adrenal axis in mice. Neurosci Lett 640: 6–12.
Li X, Morrow D, Witkin JM (2006) Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying. Life Sci 78: 1933-9.
Lin L, Chu H (2018) Quantifying publication bias in meta-analysis. Biometrics 74: 785–794.
Litvin Y, Blanchard DC, Blanchard RJ (2007) Rat 22 kHz ultrasonic vocalizations as alarm cries. Behav Brain Res 182: 166 − 72.
Liu J, Garza JC, Bronner J, Kim CS, Zhang W, Lu XY (2010) Acute administration of leptin produces anxiolytic-like effects: a comparison with fluoxetine. Psychopharmacology (Berl) 207: 535 − 45.
Louis C, Stemmelin J, Boulay D, Bergis O, Cohen C, Griebel G (2008) Additional evidence for anxiolytic- and antidepressant-like activities of saredutant (SR48968), an antagonist at the neurokinin-2 receptor in various rodent-models. Pharmacol Biochem Behav 89: 36–45.
Machado Figueiredo R, de Carvalho MC, Brandao ML, Lovick TA (2019) Short-term, low-dose fluoxetine prevents oestrous cycle-linked increase in anxiety-like behaviour in female rats. J Psychopharmacol 33: 548–557.
Makino A, Iinuma M, Fukumitsu H, Soumiya H, Furukawa Y, Furukawa S (2013) Anxiolytic-like effect of trans-2-decenoic acid ethyl ester in stress-induced anxiety-like model mice. Biomed Res 34: 259 − 67.
Manna SS, Umathe SN (2015) Paracetamol potentiates the antidepressant-like and anticompulsive-like effects of fluoxetine. Behav Pharmacol 26: 268 − 81.
Martin JR, Bos M, Jenck F, Moreau J, Mutel V, Sleight AJ, Wichmann J, Andrews JS, Berendsen HH, Broekkamp CL, Ruigt GS, Kohler C, Delft AM (1998) 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286: 913 − 24.
Matar MA, Cohen H, Kaplan Z, Zohar J (2006) The effect of early poststressor intervention with sertraline on behavioral responses in an animal model of post-traumatic stress disorder. Neuropsychopharmacology 31: 2610-8.
Matsushima Y, Shirota O, Kikura-Hanajiri R, Goda Y, Eguchi F (2009) Effects of Psilocybe argentipes on marble-burying behavior in mice. Biosci Biotechnol Biochem 73: 1866-8.
Matto V, Harro J, Allikmets L (1996) The effects of cholecystokinin A and B receptor antagonists, devazepide and L 365260, on citalopram-induced decrease of exploratory behaviour in rat. J Physiol Pharmacol 47: 661-9.
McEuen JG, Semsar KA, Lim MA, Bale TL (2009) Influence of sex and corticotropin-releasing factor pathways as determinants in serotonin sensitivity. Endocrinology 150: 3709-16.
Mesripour A, Rezaei S, Hajhashemi V (2018) Evaluating the effect of donepezil on depression and obsessive-compulsion disorder in mice models and proposing the mechanism involved. Thai Journal of Pharmaceutical Sciences 42: 1–5.
Millan MJ, Dekeyne A, Gobert A, Mannoury la Cour C, Brocco M, Rivet JM, Di Cara B, Lejeune F, Cremers TI, Flik G, de Jong TR, Olivier B, de Nanteuil G (2010) S41744, a dual neurokinin (NK)1 receptor antagonist and serotonin (5-HT) reuptake inhibitor with potential antidepressant properties: a comparison to aprepitant (MK869) and paroxetine. Eur Neuropsychopharmacol 20: 599–621.
Millan MJ, Dekeyne A, Papp M, La Rochelle CD, MacSweeny C, Peglion JL, Brocco M (2001) S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298: 581 − 91.
Millan MJ, Girardon S, Mullot J, Brocco M, Dekeyne A (2002) Stereospecific blockade of marble-burying behaviour in mice by selective, non-peptidergic neurokinin1 (NK1) receptor antagonists. Neuropharmacology 42: 677 − 84.
Mishra RK, Mishra A, Gupta A (2021) Magic Shotgun Nature with Scattergun Approach of Curcumin Repurposing in Obsessive-compulsive Disorder: A Novel Metaphysician of Drug Discovery. CNS Neurol Disord Drug Targets 20: 975–981.
Misrani A, Tabassum S, Chen X, Tan SY, Wang JC, Yang L, Long C (2019) Differential effects of citalopram on sleep-deprivation-induced depressive-like behavior and memory impairments in mice. Prog Neuropsychopharmacol Biol Psychiatry 88: 102–111.
Mitra S, Mucha M, Owen S, Bult-Ito A (2017) Postpartum Lactation-Mediated Behavioral Outcomes and Drug Responses in a Spontaneous Mouse Model of Obsessive-Compulsive Disorder. ACS Chem Neurosci 8: 2683–2697.
Morley-Fletcher S, Zuena AR, Mairesse J, Gatta E, Van Camp G, Bouwalerh H, Riozzi B, Battaglia G, Pittaluga A, Olivero G, Mocaer E, Bretin S, Nicoletti F, Maccari S (2018) The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats. Neuropharmacology 135: 284–296.
Murphy SE, Capitao LP, Giles SLC, Cowen PJ, Stringaris A, Harmer CJ (2021) The knowns and unknowns of SSRI treatment in young people with depression and anxiety: efficacy, predictors, and mechanisms of action. Lancet Psychiatry 8: 824–835.
Muthmainah M, Sari WA, Wiyono N, Ghazali DA, Yudhani RD, Wasita B (2021) Environmental Enrichment Ameliorates Anxiety-Like Behavior in Rats without Altering Plasma Corticosterone Level. Open Access Macedonian Journal of Medical Sciences 9: 1074–1080.
Nakamura K, Kurasawa M (2001) Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism. Eur J Pharmacol 420: 33–43.
Nardo M, Casarotto PC, Gomes FV, Guimaraes FS (2014) Cannabidiol reverses the mCPP-induced increase in marble-burying behavior. Fundam Clin Pharmacol 28: 544 − 50.
Naslund J, Studer E, Pettersson R, Hagsater M, Nilsson S, Nissbrandt H, Eriksson E (2015) Differences in Anxiety-Like Behavior within a Batch of Wistar Rats Are Associated with Differences in Serotonergic Transmission, Enhanced by Acute SRI Administration, and Abolished By Serotonin Depletion. Int J Neuropsychopharmacol 18.
Nelson EE, Alberts JR (2002) Gastric saline infusion reduces ultrasonic vocalizations and brown fat activity in suckling rat pups. Dev Psychobiol 40: 160-7.
Nicolas LB, Kolb Y, Prinssen EP (2006) A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. Eur J Pharmacol 547: 106 − 15.
Njung’e K, Handley SL (1991) Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br J Pharmacol 104: 105 − 12.
Noori N, Bangash MY, Motaghinejad M, Hosseini P, Noudoost B (2014) Kefir protective effects against nicotine cessation-induced anxiety and cognition impairments in rats. Adv Biomed Res 3: 251.
Offidani E, Guidi J, Tomba E, Fava GA (2013) Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom 82: 355 − 62.
Oh JE, Zupan B, Gross S, Toth M (2009) Paradoxical anxiogenic response of juvenile mice to fluoxetine. Neuropsychopharmacology 34: 2197 − 207.
Oliveira TPD, Goncalves BDC, Oliveira BS, de Oliveira ACP, Reis HJ, Ferreira CN, Aguiar DC, de Miranda AS, Ribeiro FM, Vieira EML, Palotas A, Vieira LB (2021) Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior. Front Neurosci 15: 631311.
Opbroek A, Delgado PL, Laukes C, McGahuey C, Katsanis J, Moreno FA, Manber R (2002) Emotional blunting associated with SSRI-induced sexual dysfunction. Do SSRIs inhibit emotional responses? Int J Neuropsychopharmacol 5: 147 − 51.
Padua-Reis M, Noga DA, Tort ABL, Blunder M (2021) Diazepam causes sedative rather than anxiolytic effects in C57BL/6J mice. Sci Rep 11: 9335.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hrobjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372: n71.
Pan W, Lyu K, Zhang H, Li C, Chen P, Ying M, Chen F, Tang J (2020) Attenuation of auditory mismatch negativity in serotonin transporter knockout mice with anxiety-related behaviors. Behav Brain Res 379: 112387.
Pandey SC, Zhang D, Mittal N, Nayyar D (1999) Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal-related anxiety. J Pharmacol Exp Ther 288: 866 − 78.
Pannu AS, Parle M (2017) ANTI- OBSESSIVE COMPULSIVE ACTIVITY OF HONEY. Asian Journal of Pharmaceutical and Clinical Research 10: 206–209.
Pannu AS (2017) Investigation of the Anti-obsessive Comulsive Activity of Pyrus communis Juice in Mice
Pelleymounter MA, Joppa M, Ling N, Foster AC (2002) Pharmacological evidence supporting a role for central corticotropin-releasing factor(2) receptors in behavioral, but not endocrine, response to environmental stress. J Pharmacol Exp Ther 302: 145 − 52.
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14: 149 − 67.
Pereira AC, Carvalho MC, Padovan CM (2019) Both serotonergic and noradrenergic systems modulate the development of tolerance to chronic stress in rats with lesions of the serotonergic neurons of the median raphe nucleus. Behav Brain Res 357–358: 39–47.
Pereira MM, de Morais H, Dos Santos Silva E, Corso CR, Adami ER, Carlos RM, Acco A, Zanoveli JM (2018) The antioxidant gallic acid induces anxiolytic-, but not antidepressant-like effect, in streptozotocin-induced diabetes. Metab Brain Dis 33: 1573–1584.
Pereira VS, Casarotto PC, Hiroaki-Sato VA, Sartim AG, Guimaraes FS, Joca SR (2013) Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: involvement of nitric oxide. Eur Neuropsychopharmacol 23: 1769-78.
Phadnis P, Dey Sarkar P, Rajput MS (2018) Improved serotonergic neurotransmission by genistein pretreatment regulates symptoms of obsessive-compulsive disorder in streptozotocin-induced diabetic mice. J Basic Clin Physiol Pharmacol 29: 421–425.
Poling A, Cleary J, Monaghan M (1981) Burying by rats in response to aversive and nonaversive stimuli. J Exp Anal Behav 35: 31–44.
Pollier F, Sarre S, Aguerre S, Ebinger G, Mormede P, Michotte Y, Chaouloff F (2000) Serotonin reuptake inhibition by citalopram in rat strains differing for their emotionality. Neuropsychopharmacology 22: 64–76.
Portal B, Delcourte S, Rovera R, Lejards C, Bullich S, Malnou CE, Haddjeri N, Deglon N, Guiard BP (2020) Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs. Acta Physiol (Oxf) 229: e13440.
Prajapati RP, Kalaria MV, Karkare VP, Parmar SK, Sheth NR (2011) Effect of methanolic extract of Lagenaria siceraria (Molina) Standley fruits on marble-burying behavior in mice: Implications for obsessive-compulsive disorder. Pharmacognosy Res 3: 62 − 6.
Price J, Cole V, Goodwin GM (2009) Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study. Br J Psychiatry 195: 211-7.
Pulina NA, Kuznetsov AS, Krasnova AI, Novikova VV (2019) Synthesis, Antimicrobial Activity, and Behavioral Response Effects of N-Substituted 4-Aryl-2-Hydroxy-4-Oxobut-2-Enoic Acid Hydrazides and Their Metal Complexes. Pharmaceutical Chemistry Journal 53: 220–224.
Quesseveur G, David DJ, Gaillard MC, Pla P, Wu MV, Nguyen HT, Nicolas V, Auregan G, David I, Dranovsky A, Hantraye P, Hen R, Gardier AM, Deglon N, Guiard BP (2013) BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities. Transl Psychiatry 3: e253.
Ravi G, Eerike M (2022) Screening Methods for the Evaluation of Anxiolytic Drugs. In: Lakshmanan M, Shewade DG, Raj GM (eds) Introduction to Basics of Pharmacology and Toxicology: Volume 3: Experimental Pharmacology : Research Methodology and Biostatistics. Springer Nature Singapore, Singapore, pp 241–249
Ravinder S, Pillai AG, Chattarji S (2011) Cellular correlates of enhanced anxiety caused by acute treatment with the selective serotonin reuptake inhibitor fluoxetine in rats. Front Behav Neurosci 5: 88.
Rebai R, Jasmin L, Boudah A (2017) The antidepressant effect of melatonin and fluoxetine in diabetic rats is associated with a reduction of the oxidative stress in the prefrontal and hippocampal cortices. Brain Res Bull 134: 142–150.
Regier DA, Narrow WE, Rae DS (1990) The epidemiology of anxiety disorders: the Epidemiologic Catchment Area (ECA) experience. J Psychiatr Res 24 Suppl 2: 3–14.
Reinblatt SP, Riddle MA (2006) Selective serotonin reuptake inhibitor-induced apathy: a pediatric case series. J Child Adolesc Psychopharmacol 16: 227 − 33.
Rickels K, Zaninelli R, McCafferty J, Bellew K, Iyengar M, Sheehan D (2003) Paroxetine treatment of generalized anxiety disorder: a double-blind, placebo-controlled study. Am J Psychiatry 160: 749 − 56.
Riley RD, Higgins JP, Deeks JJ (2011) Interpretation of random effects meta-analyses. BMJ 342: d549.
Robert G, Drapier D, Bentue-Ferrer D, Renault A, Reymann JM (2011) Acute and chronic anxiogenic-like response to fluoxetine in rats in the elevated plus-maze: modulation by stressful handling. Behav Brain Res 220: 344-8.
Rodgers RJ, Cutler MG, Jackson JE (1997) Behavioural effects in mice of subchronic chlordiazepoxide, maprotiline and fluvoxamine. II. The elevated plus-maze. Pharmacol Biochem Behav 57: 127 − 36.
Rodgers RJ, Dalvi A (1997) Anxiety, defence and the elevated plus-maze. Neurosci Biobehav Rev 21: 801 − 10.
Rogacki N, Lopez-Grancha M, Naimoli V, Potestio L, Stevens RJ, Pichat P, Bergis OE, Cohen C, Varty GB, Griebel G (2011) The neurokinin NK2 antagonist, saredutant, ameliorates stress-induced conditions without impairing cognition. Pharmacol Biochem Behav 98: 405 − 11.
Rogoz Z, Skuza G (2011) Anxiolytic-like effects of olanzapine, risperidone and fluoxetine in the elevated plus-maze test in rats. Pharmacol Rep 63: 1547-52.
Saadat KS, Elliott JM, Colado MI, Green AR (2006) The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice. J Psychopharmacol 20: 264 − 71.
Saitoh A, Yamaguchi K, Tatsumi Y, Murasawa H, Nakatani A, Hirose N, Yamada M, Yamada M, Kamei J (2007) Effects of milnacipran and fluvoxamine on hyperemotional behaviors and the loss of tryptophan hydroxylase-positive cells in olfactory bulbectomized rats. Psychopharmacology (Berl) 191: 857 − 65.
Saltaji H, Armijo-Olivo S, Cummings GG, Amin M, da Costa BR, Flores-Mir C (2018) Influence of blinding on treatment effect size estimate in randomized controlled trials of oral health interventions. BMC Med Res Methodol 18: 42.
Sansone RA, Sansone LA (2010) SSRI-Induced Indifference. Psychiatry (Edgmont) 7: 14 − 8.
Santos T, Baungratz MM, Haskel SP, de Lima DD, da Cruz JN, Magro DD, da Cruz JG (2012) Behavioral interactions of simvastatin and fluoxetine in tests of anxiety and depression. Neuropsychiatr Dis Treat 8: 413 − 22.
Sartori SB, Singewald N (2019) Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders. Pharmacol Ther 204: 107402.
Satish I, Joel BG (1988) Selection Models and the File Drawer Problem. Statistical Science 3: 109–117.
Savignac HM, Kiely B, Dinan TG, Cryan JF (2014) Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol Motil 26: 1615-27.
Schulz KF, Chalmers I, Hayes RJ, Altman DG (1995) Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 273: 408 − 12.
Schwarting RK, Jegan N, Wohr M (2007) Situational factors, conditions and individual variables which can determine ultrasonic vocalizations in male adult Wistar rats. Behav Brain Res 182: 208 − 22.
Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ (2013) Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106–107: 1–16.
Shafia S, Vafaei AA, Samaei SA, Bandegi AR, Rafiei A, Valadan R, Hosseini-Khah Z, Mohammadkhani R, Rashidy-Pour A (2017) Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis - related proteins in a rat model of post-traumatic stress disorder. Neurobiol Learn Mem 139: 165–178.
Shahzad N, Ahmad J, Khan W, Al-Ghamdi SS, Ain MR, Ibrahim IA, Akhtar M, Khanam R (2014) Interactions of atenolol with alprazolam/escitalopram on anxiety, depression and oxidative stress. Pharmacol Biochem Behav 117: 79–84.
Shende V, Sahane RS, Lawar M, Hamdulay N, Langote H (2012) EVALUATION OF ANTI-COMPULSIVE EFFECT OF ETHANOLIC EXTRACT OF CLITORIA TERNATEA IN MICE
Shimazaki T, Iijima M, Chaki S (2004) Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test. Eur J Pharmacol 501: 121-5.
Shoblock JR, Welty N, Fraser I, Wyatt R, Lord B, Lovenberg T, Liu C, Bonaventure P (2019) In vivo Characterization of a Selective, Orally Available, and Brain Penetrant Small Molecule GPR139 Agonist. Front Pharmacol 10: 273.
Silva MT, Alves CR, Santarem EM (1999) Anxiogenic-like effect of acute and chronic fluoxetine on rats tested on the elevated plus-maze. Braz J Med Biol Res 32: 333-9.
Singh S, Botvinnik A, Shahar O, Wolf G, Yakobi C, Saban M, Salama A, Lotan A, Lerer B, Lifschytz T (2023) Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder. Transl Psychiatry 13: 164.
Skrebuhhova T, Allikmets L, Matto V (1999) [3H]-ketanserin binding and elevated plus-maze behavior after chronic antidepressant treatment in DSP-4 and P-CPA pretreated rats: evidence for partial involvement of 5-HT2A receptors. Methods Find Exp Clin Pharmacol 21: 483 − 90.
Soares-Rachetti Vde P, de Sousa Pinto IA, Santos RO, Andre E, Gavioli EC, Lovick T (2016) Short term, low dose fluoxetine blocks estrous cycle-linked changes in responsiveness to diazepam in female rats. J Psychopharmacol 30: 1062-8.
Starr KR, Price GW, Watson JM, Atkinson PJ, Arban R, Melotto S, Dawson LA, Hagan JJ, Upton N, Duxon MS (2007) SB-649915-B, a novel 5-HT1A/B autoreceptor antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast onset activity in the rat high light social interaction test. Neuropsychopharmacology 32: 2163-72.
Stemmelin J, Cohen C, Terranova JP, Lopez-Grancha M, Pichat P, Bergis O, Decobert M, Santucci V, Francon D, Alonso R, Stahl SM, Keane P, Avenet P, Scatton B, le Fur G, Griebel G (2008) Stimulation of the beta3-Adrenoceptor as a novel treatment strategy for anxiety and depressive disorders. Neuropsychopharmacology 33: 574 − 87.
Su AS, Zhang JW, Zou J (2019) The anxiolytic-like effects of puerarin on an animal model of PTSD. Biomed Pharmacother 115: 108978.
Sugimoto Y, Tagawa N, Kobayashi Y, Hotta Y, Yamada J (2007) Effects of the serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran on marble burying behavior in mice. Biol Pharm Bull 30: 2399 − 401.
Sun T, He W, Hu G, Li M (2010) Anxiolytic-like property of risperidone and olanzapine as examined in multiple measures of fear in rats. Pharmacol Biochem Behav 95: 298–307.
Sun W, Zhang F, Wang H, Wang C, Zhou Z, Zhou Y (2020) Ginsenoside Rg1 fails to rescue PTSD-like behaviors in a mice model of single-prolonged stress. Biochem Biophys Res Commun 528: 243–248.
Takahashi T, Suzuki G, Nibuya M, Tanaka T, Nozawa H, Hatano B, Takahashi Y, Shimizu K, Yamamoto T, Tachibana S, Nomura S (2012) Therapeutic effect of paroxetine on stress-induced gastric lesions in mice. Prog Neuropsychopharmacol Biol Psychiatry 36: 39–43.
Takeuchi H, Yatsugi S, Yamaguchi T (2002) Effect of YM992, a novel antidepressant with selective serotonin re-uptake inhibitory and 5-HT 2A receptor antagonistic activity, on a marble-burying behavior test as an obsessive-compulsive disorder model. Jpn J Pharmacol 90: 197–200.
Takeuchi T, Owa T, Nishino T, Kamei C (2010) Assessing anxiolytic-like effects of selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors using the elevated plus maze in mice. Methods Find Exp Clin Pharmacol 32: 113 − 21.
Thoeringer CK, Erhardt A, Sillaber I, Mueller MB, Ohl F, Holsboer F, Keck ME (2010) Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice. J Psychopharmacol 24: 733 − 43.
Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R (2009) Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl) 204: 361 − 73.
Trofimiuk E, Braszko JJ (2013) Concomitant docosahexaenoic acid administration ameliorates stress-induced cognitive impairment in rats. Physiol Behav 118: 171-7.
Tu W, Cook A, Scholl JL, Mears M, Watt MJ, Renner KJ, Forster GL (2014) Serotonin in the ventral hippocampus modulates anxiety-like behavior during amphetamine withdrawal. Neuroscience 281: 35–43.
Uday G, Pravinkumar B, Manish W, Sudhir U (2007) LHRH antagonist attenuates the effect of fluoxetine on marble-burying behavior in mice. Eur J Pharmacol 563: 155-9.
Umathe SN, Bhutada PS, Jain NS, Mundhada YR, Borkar SS, Dhumal B (2009a) Role of nitric oxide in obsessive-compulsive behavior and its involvement in the anti-compulsive effect of paroxetine in mice. Nitric Oxide 21: 140-7.
Umathe SN, J MV, N SJ, P VD (2009b) Neurosteroids modulate compulsive and persistent behavior in rodents: implications for obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 33: 1161-6.
Umathe SN, Manna SS, Jain NS (2011) Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice. Behav Brain Res 223: 125 − 34.
Umathe SN, Manna SS, Jain NS (2012) Endocannabinoid analogues exacerbate marble-burying behavior in mice via TRPV1 receptor. Neuropharmacology 62: 2024-33.
Uz T, Dimitrijevic N, Akhisaroglu M, Imbesi M, Kurtuncu M, Manev H (2004) The pineal gland and anxiogenic-like action of fluoxetine in mice. Neuroreport 15: 691-4.
Van den Noortgate W, Lopez-Lopez JA, Marin-Martinez F, Sanchez-Meca J (2015) Meta-analysis of multiple outcomes: a multilevel approach. Behav Res Methods 47: 1274–1294.
Van Lissa CJ, Brandmaier AM, Brinkman L, Lamprecht A-L, Peikert A, Struiksma ME, Vreede BMI (2021) WORCS: A workflow for open reproducible code in science. Data Science 4: 29–49.
Van Lissa CJ, van Erp S, Clapper EB (2023) Selecting relevant moderators with Bayesian regularized meta-regression. Res Synth Methods 14: 301–322.
Varty GB, Morgan CA, Cohen-Williams ME, Coffin VL, Carey GJ (2002) The gerbil elevated plus-maze I: behavioral characterization and pharmacological validation. Neuropsychopharmacology 27: 357 − 70.
Verdouw PM, van Esterik JC, Peeters BW, Millan MJ, Groenink L (2017) CRF(1) but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine. Pharmacol Biochem Behav 154: 11–19.
Viechtbauer W (2010) Conducting Meta-Analyses in R with the metafor Package. Journal of Statistical Software 36: 1–48.
Vinkers CH, Penning R, Hellhammer J, Verster JC, Klaessens JH, Olivier B, Kalkman CJ (2013) The effect of stress on core and peripheral body temperature in humans. Stress 16: 520 − 30.
Vorhees CV, Morford LR, Graham DL, Skelton MR, Williams MT (2011) Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug. Behav Brain Funct 7: 41.
Wang LR, Kim SH, Baek SS (2019) Effects of treadmill exercise on the anxiety-like behavior through modulation of GSK3beta/beta-catenin signaling in the maternal separation rat pup. J Exerc Rehabil 15: 206–212.
Wang C, Li M, Sawmiller D, Fan Y, Ma Y, Tan J, Ren Y, Li S (2014) Chronic mild stress-induced changes of risk assessment behaviors in mice are prevented by chronic treatment with fluoxetine but not diazepam. Pharmacol Biochem Behav 116: 116 − 28.
Winslow JT, Insel TR (1991a) Infant rat separation is a sensitive test for novel anxiolytics. Prog Neuropsychopharmacol Biol Psychiatry 15: 745 − 57.
Winslow JT, Insel TR (1991b) Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists. Psychopharmacology (Berl) 105: 513 − 20.
Witkin JM (2008) Animal models of obsessive-compulsive disorder. Curr Protoc Neurosci Chap. 9: Unit 9 30.
Wu YP, Gao HY, Ouyang SH, Kurihara H, He RR, Li YF (2019) Predator stress-induced depression is associated with inhibition of hippocampal neurogenesis in adult male mice. Neural Regen Res 14: 298–305.
Yang SJ, Kim SY, Stewart R, Kim JM, Shin IS, Jung SW, Lee MS, Jeong SH, Jun TY (2011) Gender differences in 12-week antidepressant treatment outcomes for a naturalistic secondary care cohort: the CRESCEND study. Psychiatry Res 189: 82–90.
Yang Y, Zhao S, Yang X, Li W, Si J, Yang X (2022) The antidepressant potential of lactobacillus casei in the postpartum depression rat model mediated by the microbiota-gut-brain axis. Neurosci Lett 774: 136474.
Yin SH, Wang CC, Cheng TJ, Chang CY, Lin KC, Kan WC, Wang HY, Kao WM, Kuo YL, Chen JC, Li SL, Cheng CH, Chuu JJ (2012) Room-temperature super-extraction system (RTSES) optimizes the anxiolytic- and antidepressant-like behavioural effects of traditional Xiao-Yao-San in mice. Chin Med 7: 24.
Zethof TJ, Van der Heyden JA, Tolboom JT, Olivier B (1995) Stress-induced hyperthermia as a putative anxiety model. Eur J Pharmacol 294: 125 − 35.
Zimmerberg B, Germeyan SC (2015) Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait. Dev Psychobiol 57: 141 − 52.
Zorzin S, Corsi A, Ciarpella F, Bottani E, Dolci S, Malpeli G, Pino A, Amenta A, Fumagalli GF, Chiamulera C, Bifari F, Decimo I (2021) Environmental Enrichment Induces Meningeal Niche Remodeling through TrkB-Mediated Signaling. Int J Mol Sci 22.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Heesbeen, E.J., van Kampen, T., Verdouw, P.M. et al. The effect of SSRIs on unconditioned anxiety: a systematic review and meta-analysis of animal studies. Psychopharmacology 241, 1731–1755 (2024). https://doi.org/10.1007/s00213-024-06645-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-024-06645-2