Mild motor signs and depression: more than just medication side effects?

Abstract

The relationship between major depressive disorder (MDD) and mild motor signs (MMS) remains to be elucidated. The present study aims to assess the association between neurological symptoms and medications and treatment response. Neurological signs in 790 patients with MDD were correlated with treatment outcome. Three hundred ten (39.2%) were responders and 480 (60.8%) were non-responders. 342 (43.3%) presented neurological signs. In the whole sample negative associations between dystonia and rigidity and various medications was observed. Non-response was associated with dystonia, rigidity, and hypokinesia independent from age and medications. This study highlighted an association between MMS and specific medications. Moreover, MMS were associated with non-response to treatment, regardless of medication use. This may suggest that a subgroup of patients with MDD may respond less to therapy because of an underlying still undetected neurological disorder.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00406-025-02015-x.

Introduction

Over the past 30 years the global incidence of Major Depression Disorders (MDD) has increased by approximately 50%, currently affecting more than 260 million people worldwide [1].

Treatment adherence is necessary to achieve treatment response; however, patients with MDD show non-compliance rates ranging from 10% up to 60% [2, 3]. Previous studies linked poor compliance to several factors, including fears and prejudices about medications, education, social support and side effects [4]. The most common side effects of antidepressants include gastrointestinal disturbances, sexual dysfunction, sleep disorders and weight gain [5, 6]. While the incidence of secondary parkinsonism has decreased with the use of second-generation antipsychotics [7]. the possible link between antidepressants and motor symptoms remains to be clarified.

We previously identified an association between depressive features and neurological side effects in patients with MDD [8]. However, that study examined the prevalence of neurological side effects using the Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) total score without focusing on specific neurological features [8]. Furthermore, it cannot be ruled out that, rather than being directly related to medications, neurological symptoms, mild motor signs (MMS) in particular, may represent the epiphenomenon of an underlying subclinical movement disorder. In such cases, despite appropriate dosage and duration of treatment, response may not be optimal if the underlying neurological condition is not appropriately recognized and treated.

The aims of this study were:1) to assess the possible association between neurological symptoms and medications;2) to assess the possible association between response to treatment and neurological symptoms in subjects with MDD independent from treatment type.

Methods

Study sample

Subjects included in our analyses were selected from the cross-sectional European multicenter Group for the Study of Resistant Depression (GSRD). As detailed elsewhere [9], adults with a current MDD and naturalistically treated with at least one antidepressant drug at a sufficient dose for a minimum of 4-weeks were enrolled. Depression severity was assessed through the Montgomery-Åsberg Depression Rating Scale (MADRS).

Patients were classified as responders (reduction in total MADRS score ≥ 50%) or non-responders. In case of insufficient response after two or more antidepressant trials, patients were defined as having treatment-resistant depression (TRD). Previous findings indicated that overall side effects are associated with TRD, and this group has had a more complex treatment regimen,⁸ therefore patients with TRD were excluded from the present analyses, and only responders and non-responders were included. Patients with previous diagnosis of movement disorders were also excluded. In addition, scarcely represented drug classes (administered to less than 5% of the whole sample) were excluded from the analyses.

Neurological side effects were assessed through the UKU, specifically the 8-item neurological subscale [10].

All the Ethical Committees of the participating centers approved the study protocol that was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The enrolled subjects signed a written informed consent prior to participation.

Statistical analysis

T-tests and chi-square tests were used as appropriate. Logistic regression analyses were carried out to test possible associations between drug classes and neurological signs using both univariate and age-adjusted multivariate models. Then, logistic regressions were used to test the possible associations between response to treatment and the presence of neurological signs using univariate models; multivariate models were also carried out adjusting for age and the drug classes identified in the first analysis (those associated with neurological signs). A sensitivity analysis was performed excluding patients treated with antipsychotics, given the possible effects of antipsychotics on movement symptoms.

The statistical significance level was set at 0.05, uncorrected because of the high correlation among neurological subscale items. The sample had a power of 0.80 to detect a small effect size of d = 0.2 on neurological subscale items for the main analyses. Data were analyzed with STATA v.18 (StataCorp, 2023).

Data sharing

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Results

Demographic and clinical characteristics of the sample

After excluding 503 patients with TRD and one patient with a previous diagnosis of parkinsonism, a total of 790 patients with MDD [535 (67.6%) women, mean age 51.6 ± 14.2 years; episode duration 194.6 ± 192.4 days] were included (Table 1). Mean body mass index (BMI) was 25.5 ± 5.2, and 371 (48.6%) patients were smokers.

Table 1.

Demographic and clinical characteristics of the sample (n = 790)

Education (obs n. 778)
Elementary school	73 (9.4)
Secondary school	270 (34.7)
High school	198 (25.4)
University	237 (30.5)
Marital status
Married/live with	391 (49.5)
Widowed	35 (4.4)
Separated	76 (9.6)
Single	198 (25.1)
Divorced	90 (11.4)
Children	507 (64.2)
No. of children	1.2 ± 1.2
Living
Alone	229 (28.9)
At home with spouse/concubine/children	483 (61.1)
At parents or children’s home	46 (5.8)
With someone else (roommate/cousins)	27 (3.4)
With others	5 (0.6)
Work income
Unemployed/social benefit	207 (26.3)
Worker	65 (8.2)
Employed/retired/student	494 (62.7)
Management	22 (2.8)
Depression characteristics
Number of MDEs	3.4 ± 2.4
Age at first MDE, years	35.9 ± 15.3
Age at last MDE, years	47.5 ± 14.2
Lifetime illness duration, years	15.8 ± 13.2
Time of hospitalization, weeks	4.1 ± 13.1
Current MADRS score	20.2 ± 11.6

Legend: data are expressed as number and percentage or mean ± standard deviation. MDEs: mood depression episodes; MADRS: Montgomery-Åsberg Depression Rating Scale

According to MADRS scores, 310 (39.2%) patients were responders and 480 (60.8%) were non-responders. No differences were found between responders and non-responders considering age (51.3 ± 15.6 vs. 51.8 ± 13.2, p = 0.624) and sex [201 (64.8%) responder women and 334 (69.6%) non-responder women, p = 0.164]. Responders had a retrospective MADRS score significantly lower than non-responders (31.7 ± 7.7 vs. 34.4 ± 7.9, p < 0.001).

All patients were treated with antidepressants, with 241 (30.6%) also receiving benzodiazepines, 98 (12.4%) mood stabilizers, and 205 (26.0%) antipsychotics. Neurological signs were observed in 342 (43.3%) patients, with tremor (32.7%) and rigidity (19.6%) being the most frequent ones. Hypokinesia and tremor were found more frequently in men, also after adjusting for age (Table 2).

Table 2.

Neurological signs: sex differences

				Univariate analysis			Multivariate analysis (adjusted for age and drugs)
	Whole sample (n = 790)	Women (n = 535)	Men (n = 255)	OR	95% CI	p-value	OR	95% CI	p-value
Dystonia	51 (14.9)	34 (6.4)	17 (6.7)	1	0.57–1.92	0.868
Rigidity	67 (19.6)	41 (7.7)	26 (10.2)	1.4	0.81–2.29	0.234
Hypokinesia	34 (9.9)	16 (2.9)	18 (7.1)	2.5	1.23–4.91	0.011	2.5	1.24–4.94	0.010*
Hyperkinesia	19 (5.5)	12 (2.2)	7 (2.7)	1.2	0.47–3.16	0.667
Tremor	112 (32.7)	64 (11.9)	48 (18.8)	1.7	1.13–2.56	0.010	1.7	1.12–2.54	0.011*
Akathisia	31 (9.1)	18 (3.4)	13 (5.1)	1.5	0.74–3.20	0.244
Epilepsy	0
Paresthesia	28 (8.2)	15 (2.8)	13 (5.1)	1.9	0.87–3.97	0.108

Legend: data are expressed as number and percentage. OR: odds ratio; CI: confidence intervals. Bold values: p < 0.05. *Adjusted for age

Neurological signs and prescribed drug classes

Prescribed drug classes are shown in the Online Resource 1. In the univariate analysis, a negative association between dystonia and both noradrenergic and specific serotonergic antidepressants (NASSAs) and antipsychotics was observed. Similarly, a negative association between rigidity and benzodiazepines, mood stabilizers, and antipsychotics was found. Moreover, a negative association between akathisia and benzodiazepines was found. These associations were confirmed in the analysis adjusted for age (Online Resource 2).

Neurological signs and response to treatment

Univariate analysis showed a positive association between non-response and the presence of dystonia, rigidity, and hypokinesia. These associations were confirmed after adjusting for age and prescribed drug class(es) (see Online Resource 3).

A sensitivity analysis considering patients not taking antipsychotics (n = 582) confirmed the associations between non-response, dystonia (OR 3.5;95%CI 1.60–7.68; p = 0.002), rigidity (OR 4.6; 95%CI 2.20–9.44; p < 0.001) and hypokinesia (OR 4.3;95%CI 1.24–14.63; p = 0.021).

Discussion

In our cohort, more than 40% of subjects with MDD reported neurological signs, particularly tremor and rigidity. This finding is particularly noteworthy, considering that MMS are not commonly recognized as side effects of antidepressants [11].

Few studies assessed the association between MMS and antidepressants, reporting an association between extrapyramidal symptoms and serotonergic antidepressants [12]. However, the heterogeneity of the motor signs assessed and the frequent use of antipsychotics and mood stabilizers in comedication may reduce the informativeness of existing studies [13, 14].

The pharmacological mechanism underlying the occurrence of MMS in patients treated with antidepressants still needs to be clarified. The increased serotonin availability could down-regulate the striatal dopaminergic release [15]. However, in our cohort, no association between MMS and SSRIs, SNRIs, SARIs, and TCAs was found, supporting that the neurological side effects of these medications are infrequent. Instead, a negative association between NASSAs, antipsychotics and dystonia was found. Concerning NASSAs, this finding could be related to blockade of the presynaptic α2-adrenergic receptors on noradrenergic and serotonergic nerve terminals, to the inhibition of the 5-HT2 and 5-HT3 receptors and the indirect stimulation of the 5-HT1A receptors, leading to an upregulation of the protective antioxidative mechanisms in dopaminergic neurons [16].

Although literature consistently reports a positive association between D2 receptor-blocking drugs and motor signs [17], in our cohort antipsychotics were negatively associated with rigidity and dystonia. This seemingly surprising finding may be related to the prevalent use of quetiapine at low doses, whose extrapyramidal side effects have been previously defined as negligible compared to other antipsychotics [18–21].

Finally, a negative association was found between benzodiazepines, mood stabilizers and rigidity. Although conflicting literature data still exist [22, 23], our finding may be related to the GABAergic effect of both benzodiazepines [24], lithium [25], lamotrigine [26], gabapentin [27], and valproic acid [28], which were the most prescribed mood stabilizers in our cohort.

Although MMS have been clearly associated with old age [29, 30], we did not find any association between MMS and age (data not shown). This finding may be related to the relatively young mean age of our cohort (about 50 years old). In addition, considering sex differences, extrapyramidal signs were more frequent in men than women, and a strong association between hypokinesia and tremor was found in men.

In line with what we previously reported [8], our cohort of non-responders presented a more severe clinical phenotype. Moreover, our findings are of interest because they may suggest the existence of a subtle neurodegenerative disorder underpinned by basal ganglia abnormalities in patients suffering from depression [31, 32]. Interestingly, depression is one of the most common non-motor symptoms of Parkinson’s disease (PD), with a prevalence of around 40% even in the pre-motor phases of the disease [33]. Indeed, psychomotor retardation and mild extrapyramidal signs, similar to those observed in PD patients, have been frequently reported in patients with MDD [34, 35]. Moreover, a strong association between difficult-to-treat depression and later incident PD with a time-dependent effect has been reported, suggesting depression as a very early prodromal non-motor symptom or even a risk factor for PD [36].

Moreover, a negative correlation between MDD and dopamine transporter availability [37] and putamen volumes have been reported [38].

Notably, a strong association between dystonia, rigidity, hypokinesia and lack of response to treatment was found, regardless of age and medications. The higher prevalence of treatment-unrelated MMS in non-responders (particularly men) raises intriguing considerations that may be of clinical value. In particular, one could speculate that a subgroup of patients may not respond to treatment because their underlying condition might be a pre-clinical non-motor feature of PD, which is more common in men [39]. However, on the other hand, lack of response could be related to a poorer treatment adherence in patients who have developed adverse effects, including extrapyramidal symptoms.

Some limitations should be considered. The lack of a baseline neurological evaluation and a direct measure of treatment adherence does not allow to determine the direct relationship between MMS and treatments. Additionally, this study lacks information on REM sleep behavior disorder, linked to both antidepressants and parkinsonism [40]. Moreover, neurological signs were assessed by a questionnaire rather than by an expert in movement disorders, which may reduce the diagnostic accuracy.

Our study shows the high prevalence of MMS in MDD patients, especially in non-responders and men. These motor signs are not just side effects of antidepressants. MMS in MDD patients need closer attention and further study as potential early indicators of neurodegenerative disorders.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

AL: Statistical Analysis: Design, Execution, Review and Critique, Manuscript: Writing of the first draft, Review and Critique; ML: Statistical Analysis: Review and Critique, Manuscript: Review and Critique; SK: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; JZ: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; DS: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; SM: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; PF: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; DR: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; JM: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; RZ: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; RF: Statistical Analysis: Review and Critique, Manuscript: Review and Critique; BL: Statistical Analysis: Review and Critique, Manuscript: Review and Critique; BP: Statistical Analysis: Review and Critique, Manuscript: Review and Critique; BTB: Research project: Conception, Organization, Execution, Manuscript: Review and Critique; GF: Statistical Analysis: Review and Critique, Manuscript: Review and Critique; CF: Statistical Analysis: Review and Critique, Review and Critique; AS: Research project: Conception, Organization, Execution, Statistical Analysis: Design, Review and Critique, Manuscript: Review and Critique.

Fuingnd

Dr. Rujescu served as consultant for Janssen, received honoraria from Boehringer-Ingelheim, Gerot Lannacher, Janssen and Pharmagenetix, received research/ travel support from Angelini, Boehringer-Ingelheim, Janssen and Schwabe, and served on advisory boards of AC Immune, Boehringer-Ingelheim, Roche and Rovi. Dr. Souery has received grant/research support from GlaxoSmithKline and Lundbeck; and he has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Lundbeck. Dr.Mendlewicz is a member of the board of the Lundbeck International Neuroscience Foundation and of the advisory board of Servier. Dr. Zohar has received grant/research support from Lundbeck, Servier, and Pfizer; he has served as a consultant or on the advisory boards for Servier, Pfizer, Solvay, and Actelion; and he has served on speakers’ bureaus for Lundbeck, GlaxoSmithKline, Jazz, and Solvay. Dr. Montgomery has served as a consultant or on advisory boards for AstraZeneca, Bionevia, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Grunenthal, Intellect Pharma, Johnson & Johnson, Lilly, Lundbeck, Merck, Merz, M’s Science, Neurim, Otsuka, Pierre Fabre, Pfizer, Pharmaneuroboost, Richter, Roche, Sanofi, Sepracor, Servier, Shire, Synosis, Takeda, Theracos, Targacept, Transcept, UBC, Xytis, and Wyeth. Dr. Serretti has served as a consultant or speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier and Taliaz. Dr. Kasper has received grant/research support from Lundbeck; he has served as a consultant or on advisory boards for Angelini, Biogen, Esai, Janssen, IQVIA, Lundbeck, Mylan, Recordati, Sage and Schwabe; and he has served on speakers bureaus for Aspen Farmaceutica S.A., Angelini, Biogen, Janssen, Lundbeck, Neuraxpharma, Recordati, Sage, Sanofi, Schwabe, Servier and Sun Pharma. Dr. Baune received honoraria for serving as a consultant or on advisory boards for Angelini, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Meyers Squibb, Janssen, LivaNova, Lundbeck, Medscape, Neurotorium, Novartis, Otsuka, Pfizer, Recordati, Roche, Rovi, Sanofi, Servier, Teva. The other authors declare no potential conflicts of interest.

Declarations

Financial disclosures

The European Group for the Study of Resistant Depression (GSRD) obtained an unrestricted grant sponsored by Lundbeck A/S. The sponsor played no role in designing the study, data collection and analyses, interpretation of the data, writing of the manuscript, and in the decision to submit the research for publication. Bernhard T Baune, Chiara Fabbri, Alessandro Serretti received support from Psych-STRATA, a project funded from the European Union’s Horizon Europe research and innovation program under Grant Agreement No. 101,057,454.

Competing interests

The authors report there are no competing interests to declare.