The role of neuroactive steroids in tic disorders

Abstract

Tics are sudden, repetitive movements or vocalizations. Tic disorders, such as Tourette syndrome (TS), are contributed by the interplay of genetic risk factors and environmental variables, leading to abnormalities in the functioning of the cortico-striatal-thalamo-cortical (CSTC) circuitry. Various neurotransmitter systems, such as gamma-aminobutyric acid (GABA) and dopamine, are implicated in the pathophysiology of these disorders.

Building on the evidence that tic disorders are predominant in males and exacerbated by stress, emerging research is focusing on the involvement of neuroactive steroids, including dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone, in the ontogeny of tics and other phenotypes associated with TS.

Emerging evidence indicates that DHEAS levels are significantly elevated in the plasma of TS-affected boys, and the clinical onset of this disorder coincides with the period of adrenarche, the developmental stage characterized by a surge in DHEAS synthesis. On the other hand, allopregnanolone has garnered particular attention for its potential to mediate the adverse effects of acute stress on the exacerbation of tic severity and frequency. Notably, both neurosteroids act as key modulators of GABA-A receptors, suggesting a pivotal role of these targets in the pathophysiology of various clinical manifestations of tic disorders.

This review explores the potential mechanisms by which these and other neuroactive steroids may influence tic disorders and discusses the emerging therapeutic strategies that target neuroactive steroids for the management of tic disorders.

INTRODUCTION

Tic disorders are characterized by rapid motor and vocal manifestations typically preceded by uncomfortable feelings and urges. The initial documented account of tic disorders dates back to 1825, when the French neurologist Jean-Gaspard Itard published the clinical case of “Madame D.” (whose real identity was Ernestine Émilie Prondre de Guermantes, Countess Picot de Dampierre), a noblewoman who gained notoriety for her involuntary movements and obscene verbal outbursts within the social gatherings of the salons of the contemporary Parisian aristocracy (Walusinski and Féray, 2020). Six decades later, Georges Gilles de la Tourette included this case into a comprehensive report featuring eight additional patients with similar symptomatology and clinical characteristics, including a likely hereditary origin, childhood onset, and male preponderance (Lajonchere et al., 1996). This condition, eponymously named “Tourette Syndrome” (TS), was long regarded as a rare neuropsychiatric oddity. However, following the discovery in the 1960’s of the therapeutic effects of antipsychotic medications in TS, a new wave of research revealed that tics are far more prevalent than initially postulated. The past few decades have witnessed substantial advancements in our understanding of the genetic, environmental, and neurobiological factors contributing to the pathophysiology of TS, as well as the development of novel treatments.

Despite this progress, current treatments continue to fall short of providing satisfactory outcomes for many affected individuals, and substantial knowledge gaps persist on the biological mechanisms underlying tics. In particular, recent lines of evidence have recently brought into focus the potential role of neuroactive steroids as modulators of tic disorders and potential sources for novel therapeutic strategies. These endogenous molecules, which are produced by adrenal glands, gonads, and the central nervous system are critical in regulating several neurobehavioral functions, including sex-specific traits and stress reactivity (for a general overview of the major steroid families and their biosynthetic pathways, see Figure 1; (Frye, 2009; Mellon and Griffin, 2002). Building on these premises, emerging evidence indicates a likely role of these mediators in the modulation of tics and other phenotypes related to TS.

Figure 1:

The first step in steroidogenesis is the movement of cholesterol, which is sourced either through its own synthesis or from the breakdown of lipoproteins, into the mitochondria. This movement is initiated by the steroidogenic acute regulatory protein (StAR). Following this, cholesterol undergoes conversion into pregnenolone. This transformation involves three consecutive monooxygenase reactions facilitated by the enzyme cytochrome P450 side-chain cleavage (CYP11A1). The subsequent fate of pregnenolone is determined by the specific enzymes present within the cell, leading to its various metabolic pathways.

Although there is a wide variety of steroid metabolites, the metabolic processes of steroidogenesis are carried out by a relatively small group of enzymes, which include the following families: 3β-hydroxysteroid dehydrogenase (3β-HSD), 5α-reductase (5αR), 3α-hydroxysteroid dehydrogenase (3α-HSD), 17,20 desmolase-lyase (CYP17A1), 17β-hydroxysteroid dehydrogenase (17β-HSD), and aromatase (for more information, see (Payne and Hales, 2004).

While the full functional implications of the production of a wide array of biologically active steroids are not yet completely comprehended, their effects are known to be linked with the modulation of receptors within the cytoplasm and on cell membranes. Different steroids, such as estrogens, androgens, progestogens, glucocorticoids, and mineralocorticoids, are synthesized by various glands, including the gonads and adrenal cortices. These steroids play crucial roles in regulating reproductive functions as well as in managing stress and metabolic responses (Payne and Hales, 2004). In addition, stress responses are regulated by notable neurosteroids such as allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP), tetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one; THDOC), and 3α-androstanediol (5α-androstane-3α,17β-diol).

Orange: progestogens, gray: neurosteroids, pink: estrogens, cyan: androgens, light green: corticosteroid, dark green: mineralcorticoids.

The aim of this review is to provide an overview of the role of neuroactive steroids and the course and pathophysiology of tic disorders. To this end, here we present a general summary of all relevant evidence, as identified in key scientific databases, including Pubmed, PsycINFO, and Medline. We will first describe clinical characteristics, genetic and neurobiological factors, and therapeutic strategies relevant to these conditions. Subsequently, we will discuss the available evidence on the observed abnormalities in neuroactive steroids described in tic disorders. Finally, we will delineate a set of potential mechanisms whereby the implication of these molecules may help explain some unresolved questions on the course and presentation of TS and indicate how steroid pathways may provide new therapeutic avenues for tic disorders.

CLINICAL CHARACTERISTICS OF TICS AND TIC DISORDERS

As mentioned above, tics are rapid, non-rhythmic, partially suppressible muscle movements resulting in motor jerks or vocalizations. Based on the degree of muscular involvement, tics are classified into simple or complex. Simple tics are due to the contraction of one muscular group and are generally manifested as brief, abrupt, and purposeless twitches; typical examples include eye blinking, neck tilting, shoulder shrugging, coughing, throat clearing, tongue clicking, etc. Conversely, complex tics typically encompass coordinated movement patterns leading to seemingly purposeful actions (like inappropriate touching, tapping, waving, jumping, smelling objects, etc.), words, or phrases. A particular type of complex tics is exemplified by echophenomena and coprophenomena, which involve the imitation of behavioral sequences (echopraxia) or phrases (echolalia) or the expression of offensive or vulgar language (coprolalia) or socially inappropriate gestures (copropraxia).

One of the key distinguishing characteristics of tics is that they are typically preceded by uncomfortable feelings, named sensory phenomena (Crossley and Cavanna, 2013; Houghton et al., 2014). The best-defined among these sensations is the premonitory urge, often described as a distressing sensation or tension building up in a specific body part (Leckman et al., 1993), which is temporarily relieved when tics are executed. The intensity of these phenomena is correlated with tic severity (Kyriazi et al., 2019). While individuals can consciously inhibit the expression of tics for some time, doing so exacerbates the severity and pervasiveness of premonitory urges.

In most cases, tics typically appear between 5 to 9 years of age, manifesting as simple vocalizations or motor jerks in the face, head, and neck (Black et al., 2021). Tic severity tends to increase with age, typically reaching its peak between 10 and 12 years (Black et al., 2021; Bloch and Leckman, 2009). From puberty onwards, many patients experience a gradual improvement in the severity of their tics (Bloch and Leckman, 2009; Groth et al., 2017). It is estimated that less than 25% of individuals with a history of tic disorder during childhood continue to have moderate or severe tics in adulthood (Black et al., 2021; Leckman et al., 1998). However, high tic severity in late childhood is a strong predictor of the persistence of tics into adulthood (Bloch et al., 2006). Aside from these diachronic variations in severity, tics also exhibit marked fluctuations, with a cyclical pattern that can be influenced by external factors like stress, fatigue, sleep deprivation, etc. (Godar and Bortolato, 2017).

According to the current diagnostic framework outlined in the DSM-5 (American Psychiatric Association, 2022), there are three distinct tic disorders:

• Tourette Syndrome (TS) or Tourette disorder: This condition is diagnosed based on two or more motor tics and at least one vocal tic appearing before age 18 and persisting for a minimum of one year.

• Persistent (or chronic) motor or vocal tic disorder: This disorder involves the presence of one or more motor or vocal tics emerging before age 18 and persisting for at least one year.

• Provisional tic disorder: This category encompasses individuals who experience one or more tics with onset before age 18 but lasting no longer than one year.

Individuals who do not entirely satisfy the criteria for any of these tic disorders, such as those whose tics start after reaching 18 years of age, are diagnosed within the classifications of either “other specified” or “unspecified” tic disorders (depending on whether the specific features of the diagnosis are defined or not).

Current estimates suggest that tics occur in 11–20% of school-age children (Scahill et al., 2014) and the prevalence rate of TS in the pediatric population is between 0.3 and 0.9% (Knight et al., 2012; Scharf et al., 2015). In contrast, adult prevalence is estimated at 0.01–0.05% (Knight et al., 2012; Levine et al., 2019). These epidemiological findings align with the observed decline in tic severity and frequency associated with aging.

It is important to acknowledge that despite their distinct categorization in the DSM-5, these disorders likely exist on a continuous spectrum concerning their underlying biological mechanisms and clinical presentation.

ETIOLOGY AND PATHOPHYSIOLOGY OF TIC DISORDERS

The etiology of tic disorders involves complex interactions between multiple genetic and environmental factors. Attesting to the strong genetic basis of TS, the heritability of this disorder has been assessed to be between 0.58 and 0.77 (Davis et al., 2013; Mataix-Cols et al., 2015), and its concordance rate among monozygotic twins is estimated at 53–56% (Hyde et al., 1995; Price et al., 1985), and is likely higher when considering the concordance with chronic tic disorders (Pedersen et al., 2022). Although ample evidence suggests the polygenic nature of TS and other tic disorders (Yu et al., 2019) and several candidate susceptibility genes have been identified for TS, confirmation is often limited by small sample sizes and clinical heterogeneity of affected individuals (Georgitsi et al., 2016).

In addition to genetic vulnerability factors, various studies have explored the influence of different environmental components among potential causal factors for tics. Based on preliminary evidence pointing to associations between tics and stress during pregnancy (Leckman et al., 1990), as well as low Apgar scores (Burd et al., 1999), several studies have explored the potential influence of pre- and peri-natal factors in increasing the risk of tic disorders. The results of these studies have pointed to associations between TS risk and parity (Mathews et al., 2014), inadequate weight gain during pregnancy and low weight at birth (Chao et al., 2014; Mathews et al., 2014), use of alcohol and cannabis during pregnancy (Mathews et al., 2014), and prenatal exposure to tobacco smoke (Ayubi et al., 2021 and Browne et al., 2016, but see Chen et al., 2023 and Mathews et al., 2014 for contradictory results). Accumulating evidence also suggests a significant role of early inflammatory events and impaired immune responses as potential cofactors in the ontogeny of tic disorders (Weidinger et al., 2014).

Although the exact molecular mechanisms of tics remain largely unknown, ample evidence suggests that tics stem from dysregulations within the cortico-striato-thalamo-cortical (CSTC) circuitry (Leckman et al., 2010), which governs the selection and initiation of movements. The synchronized activity of the CSTC pathway enables the execution of habitual actions (Berke et al., 2004). Conversely, it is believed that overactivity within this circuit contributes to the development of tic disorders and OCD (Calzà et al., 2019; Saxena and Rauch, 2000). Providing a detailed explanation of the tic mechanism is outside the purview of this review. In this paragraph, we will briefly summarize key concepts regarding the pathophysiology of various tic disorders. For a more comprehensive account of TS neurobiology, please see the reviews by Leckman et al. (2010) and Felling & Singer (2011).

The dorsal striatum (which includes the caudate and the putamen) plays a pivotal role in regulating CSTC pathway activity by orchestrating the interactions between two distinct populations of GABAergic striatal projection neurons (SPNs): the D1-SPNs and the D2-SPN, expressing D1 and D2 dopamine receptors, respectively (Gerfen and Keefe, 1994). By sending inhibitory projections to other nuclei of the basal ganglia, these cells facilitate motor behavior via the direct pathway and inhibit it via the indirect pathway, respectively (Albin et al., 1989) (see Figure 2). Several factors are critical to shape the activity of D1- and D2-SPNs, including the activity of several interneuron families, including cholinergic interneurons (CINs), parvalbumin-expressing GABAergic interneurons (PVINs), calretinin-expressing GABAergic interneurons (CRINs), and somatostatin-neuropeptide Y-nitric oxide synthase 1-expressing interneurons (SNNINs).

Figure 2:

In the direct pathway, D1-SPNs promote motor behavior by actively inhibiting GABAergic output nuclei – the internal globus pallidus (GPi) and substantia nigra pars reticulata (SNr) – which in turn project to thalamocortical and brainstem motor circuits. The reduction in inhibitory signals leaving the basal ganglia results in the disinhibition of these circuits, allowing them to execute the commands necessary for movement. Conversely, in the indirect pathway, D2-SPNs project inhibitory signals to the external globus pallidus (GPe), which then exerts inhibitory control over GPi/SNr neurons by reducing the function of the subthalamic nucleus (STN). This ultimately leads to heightened activity in the basal ganglia’s output nuclei, resulting in the suppression of thalamocortical circuitry and motor inhibition.

Growing consensus supports that tics arise from “aberrant disinhibition foci” in the dorsal striatum or, potentially, other areas of the CSTC circuit (Albin and Mink, 2006). These foci are thought to result from either excessive activation or insufficient inhibition of small clusters of SPNs. One of the best mechanisms to account for the formation of these areas is the loss of function of specific interneuron families, leading to uncontrolled activity of SPNs. Indeed, postmortem studies in high-severity TS-affected subjects have shown a decrease in the number of CINs, PVINs, and SNNINs in the dorsal striatum (Kalanithi et al., 2005; Kataoka et al., 2010; Lennington et al., 2016).

Another factor that may contribute to the formation of aberrant foci and tics is the overactivation of dopaminergic neurotransmission or signaling in the nigrostriatal pathway. Specifically, dopamine can activate the direct pathway by stimulating D₁ receptors or inhibit the indirect pathway by stimulating D₂ receptors. Increased dopaminergic activity may arise from imbalances in tonic and phasic dopamine actions or heightened dopamine receptor sensitivity (Buse et al., 2013; Gilbert et al., 2006; Maia and Conceição, 2018; Segura and Strafella, 2013; Singer et al., 2002).

In addition to dopaminergic nigrostriatal projections from the midbrain, striatal cells receive inputs from other brain regions within the CSTC circuitry, including the cortex and the thalamus. The transient overactivation of the connectivity between these regions and the striatum can also result in tics (Ramkiran et al., 2019).

TREATMENT OF TIC DISORDERS

When tics lead to physical, emotional, or poor social adjustment, behavioral and pharmacological treatment should be considered to reduce tic severity and improve the patient’s overall quality of life. Behavioral interventions, such as the Comprehensive Behavioral Intervention for Tics (CBIT), are the first-line treatment for tics. CBIT integrates psychoeducation and relaxation training with habit reversal therapy, which trains patients to become more aware of their tics and develop competing responses that suppress them over prolonged periods. When behavioral therapies are ineffective or unavailable, pharmacological interventions are recommended. First-tier medications include non-dopaminergic agents with moderate efficacy and fewer severe side effects, such as the α2-adrenergic agonists clonidine and guanfacine. Second-tier medications, namely dopamine receptor-blocking agents, are more effective in suppressing tics but come with a higher risk of side effects, including extrapyramidal symptoms (akathisia, dystonia, rigidity-bradykinesia, tardive dyskinesia), sedation, metabolic syndrome, and cardiovascular complications (torsades de pointes, QTc prolongation, myocarditis, and cardiomyopathy).

Three medications are approved by the U.S. Food and Drug Administration (FDA) for tic treatment: haloperidol, pimozide, and aripiprazole. While haloperidol and pimozide are typical antipsychotics (D₂ receptor antagonists), aripiprazole is an atypical antipsychotic due to its mechanism of action as partial D₂ receptor agonist, which offers a safer cardiovascular profile and higher tolerability.

Severe cases of TS may receive a recommendation for deep brain stimulation (DBS), a neurosurgical procedure involving the implantation of a neurostimulator device to deliver electrical stimulation to specific brain regions. DBS leads to symptom improvements in over 50% of patients (Johnson et al., 2019). Adverse events include dysarthria, paresthesia, intracranial hemorrhage, and infection (Martinez-Ramirez et al., 2018).

ANIMAL MODELS OF TIC DISORDERS

Rodent models allow researchers to explore the biological underpinnings of tic disorders in a controlled experimental environment. Key benefits of using animal models include the ability to test theories about the neurobiology of tics, examine the effects of genetic and environmental factors, and develop new drug treatments. The effectiveness of an animal model in tic disorder research hinges on three main levels of validity:

• face validity: the similarity between animal behaviors and human tic symptoms;

• construct validity: the alignment of causal factors and neurobiological mechanisms in animal models with those observed in tic disorders;

• predictive validity: response of animal models to treatments used for tic disorders.

The concept of face validity in animal models for TS is centered on comparing the resemblance between the animals’ behavioral responses and tic or other signs or symptoms of TS. In contrast with clinical terminology, the term “stereotypies” in rodents is used to designate any repetitive behaviors (Bortolato and Pittenger, 2017). Tic-like stereotypies in mice and rats include brief and sporadic (~ 0.2 / min) head or body jerks, grooming, digging, chewing, and rearing, which often arise in response to environmental stress. In addition to tic-like behaviors, a comprehensive phenotypic evaluation of the behavioral alterations in animal models of tic disorders include other behavioral domains akin to the manifestations exhibited by TS patients, such as the deficits of the prepulse inhibition (PPI) of the startle reflex. This response is the reduction of the startle response occurring when the eliciting stimulus is immediately preceded by a weaker signal. Both tic-like movements and PPI deficits share common neurobiological mechanisms with tics, based on the activation of the CSTC circuitry.

The construct validity is measured against the correspondence of etiological factors and mechanisms in these animal models and in tic disorders. Several mouse models have been generated to mimic genetic mutations associated with TS (see Table 1). Most of these mutants show behavioral and other phenotypical changes associated with tic disorders.

Table 1:

Main genetic mouse models of tic disorders.

Targeted gene	Reference
Nrxn1	(Etherton et al., 2009)
Sltrk1	(Katayama et al., 2010)
Met	(Martins et al., 2011)
Cntnap2	(Karayannis et al., 2014; Penagarikano et al., 2011)
Hdc	(Baldan et al., 2014)
Immpl2	(Kreilaus et al., 2019; Leung et al., 2023)
Ashl1	(Liu et al., 2020)
Celsr3	(Cadeddu et al., 2023a)

Other models have directly reproduced pathophysiological mechanisms in rodents and non-human primates (NHP) by attempting to generate disinhibition foci in the striatum. In this regard, the gold standard to obtain ‘tic-like’ responses in NHP and rodents is obtained via unilateral microinjections of GABA-A receptor antagonists (such as bicuculline and picrotoxin) in the dorsal striatum (Vinner et al., 2017; Worbe et al., 2013). By reducing local inhibitory action from GABAergic interneurons, this manipulation leads to non-rhythmic, myoclonic movements in the contralateral side of the body, which bear a striking resemblance to tics and follow a somatotopic pattern. Using a similar theoretical framework, specific families of interneurons have been depleted in mice, such as CINs (Cadeddu et al., 2023b; Xu et al., 2015), PVINs (Xu et al., 2016), or both (Rapanelli et al., 2017). These studies have shown that selective depletion of different interneuron families leads to varied behavioral responses under stress or stimulant exposure, suggesting that tics might emerge under conditions overriding homeostatic mechanisms.

Another key model to mimic hyperactivation of aberrant striatal foci is produced through the use of pharmacological agonists of D₁ and D₂ receptors. Animal models have shown that activation of dopamine receptors leads to stereotyped behaviors and can impair PPI, with different effects depending on the specific dopamine receptor and the animal model used (Doherty et al., 2008; Mosher et al., 2016).

A fourth class of models of tic pathophysiology is based on the use of animals with neuro potentiation of the cortex (and, in particular, the sensorimotor area, which is directly implicated in tic ontogeny). For example, low doses of picrotoxin (which reduce local inhibition by blocking GABA-A receptors) in sensorimotor cortices induce tic-like behaviors and high exploratory activity (Pogorelov et al., 2015). The best example of this mechanism, however, is afforded by D1CT-7 mice, which feature potentiated D1-positive neurons in the somatosensory cortex and in the intercalated nucleus of the amygdala (Nordstrom and Burton, 2002). These mice exhibit sudden tic-like jerks, which are more pronounced in males and emerge from early postnatal life (Nordstrom and Burton, 2002). These animals also exhibit deficits in PPI, sensorimotor integration, heightened sensitivity to touch and stress (Godar et al., 2016), and a greater propensity to engage in aggression (Nordstrom and Burton, 2002). These behaviors are more pronounced in males and follow a developmental trajectory, with onset in adolescence.

The predictive validity of an animal model for TS is determined by its ability to replicate the therapeutic effects of the TS-approved drugs, particularly antipsychotics and α2 agonists, in reducing tic-like behaviors or related symptoms. Among animal models, D1CT-7 mice have shown considerable predictive validity for TS treatments, responding to antipsychotics, α2 agonists, and D1 receptor antagonists (Godar et al., 2016). We also showed that these treatments reduce tic-like behaviors and reverse PPI deficits in CIN-d mice (Cadeddu et al., 2023b) and CELSR3 mutants (Cadeddu et al., 2023a).

THE ROLE OF SEX STEROIDS IN TIC DISORDERS

Similar to other neurodevelopmental disorders (May et al., 2019), TS is characterized by a conspicuous sexual dimorphism. Tics are more commonly observed in boys than girls, with a male-to-female ratio ranging from 3–4:1 in the pediatric population (Jin et al., 2005; Khalifa and von Knorring, 2003; Kraft et al., 2012; Snider et al., 2002; Stefanoff et al., 2008). Notably, this gender ratio gradually decreases (Garcia-Delgar et al., 2022; Garris and Quigg, 2021). This reduction is due to a diminishing prevalence of TS in boys older than 12 years, in contrast to a relative constancy - or even a modest elevation - in prevalence among girls and women (Schlander et al., 2011; Yang et al., 2016). Several studies show that females with TS have a later clinical onset and symptom peak than males (Hirschtritt et al., 2015; Kreilaus et al., 2019; Shprecher et al., 2014), lower lifetime frequency of simple tics (Santangelo et al., 1994), and milder tic severity in the age range 3–16 years (Garcia-Delgar et al., 2022). In addition, women are more likely than men to experience increased tic severity and an expansion of the body regions affected by tics (Lichter and Finnegan, 2015). Finally, in contrast to their male counterparts, female patients with TS are less frequently diagnosed with ADHD, disruptive behavior, and autism spectrum disorder (Freeman et al., 2007; Garcia-Delgar et al., 2022; Hirschtritt et al., 2015), but show a higher prevalence of anxiety disorders (Rodgers et al., 2014) and OCD (Lewin et al., 2012).

Several studies have addressed the hypothesis that the sex-related differences in tic disorders may be rooted in genetic factors. Although the most likely mode of inheritance of TS and chronic tic disorders is not sex-specific, X-linked factors were occasionally shown to serve as phenotypic modifiers and may contribute to the male predominance of tic disorders (Comings and Comings, 1986; Wang et al., 2023). In addition to these variables, several lines of evidence suggest a potential link with sex steroid hormones, which may have a different impact on key neurotransmitter systems, such as dopamine. Indeed, sex × gene interactions are posited to influence the course of other neuropsychiatric disorders, such as schizophrenia (Godar and Bortolato, 2017).

The initial indication of a crucial role of androgens in TS was based on the case of two male athletes with TS, who experienced a worsening of their symptoms in early adulthood after misusing high doses of anabolic steroids with a strong androgenic component. Interestingly, both individuals showed improvement upon cessation of the androgens, suggesting a direct link between androgens and tic severity. Further exploring this connection, Peterson and colleagues (1998) conducted a controlled study using flutamide, a drug that blocks androgen receptors. This study involved 13 adult TS patients (10 males and 3 females) and was conducted as a double-blind, placebo-controlled trial. The results showed a significant reduction in the severity of motor, but not phonic, tics. However, the beneficial effects of flutamide were not long-lasting, possibly due to a compensatory rise in testosterone levels. Complementing this, a study by Izmir and Dursun (1999) reported positive outcomes using cyproterone acetate, a strong antiandrogen. In support of these findings, a previous study on small group of TS-affected children and adolescents showed significant increases in the concentrations of testosterone (Erbay et al., 2016).

While these observations appear to support a potential role of testosterone in tic ontogeny, this theory is challenged by several premises. First, the peak severity of tics in individuals with TS typically occurs between the ages of 10 and 12, after which symptoms often decrease in severity. However, it is important to note that testosterone levels in the body significantly increase after puberty. If testosterone were a significant factor in worsening tics, one might expect puberty to increase, rather than decrease, tic severity. Second, preliminary reports showed a reduction in tic severity following treatment with clomiphene citrate (Sandyk et al., 1987), a drug that stimulates testosterone synthesis by promoting the activity of the hypothalamus-pituitary-gonad (HPG) axis.

The observed elevation of testosterone levels may be interpreted as reflective of heightened HPG activity. However, in a study conducted on 17 TS patients (14 of which were males), Sandyk and colleagues (1988) found low levels of baseline luteinizing hormone (LH). Given that the secretion of this hormone is regulated by testosterone via negative feedback (Tilbrook and Clarke, 2001), these data suggest that the overproduction of androgens in TS is likely to reflect intrinsic regulatory mechanisms rather than external stimulation from the HPG axis.

As shown in Figure 1, the synthesis of testosterone from cholesterol is based on a series of enzymatic reactions involving four key steroid-metabolizing enzymes. The initial rate-limiting step in the synthesis of all steroid hormones is the conversion of cholesterol into pregnenolone, which is mediated by the mitochondrial enzyme known as cholesterol side chain cleavage P450scc. Pregnenolone is converted into dehydroepiandrosterone (DHEA; 3β-hydroxy-5-androsten-17-one) by the enzyme cytochrome P450c17, which is responsible for two metabolic steps: the 17α-hydroxylase reaction, converting pregnenolone into 17-OH pregnenolone; and the 17,20-lyase reaction, transforming 17-OH pregnenolone into DHEA (Auchus, 2004; Miller, 2002). DHEA is then converted into androstenedione and testosterone by the sequential action of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD).

Following its production, over 99% of DHEA is converted into its sulfate form, DHEAS, by hydroxysteroid sulfotransferase (SULT2A1). This conversion enhances DHEA’s water solubility, facilitates its release into the bloodstream, and extends its half-life from approximately 30 minutes to between 7 to 10 hours. DHEAS is efficiently transported across the blood-brain barrier, where it undergoes desulfation by steroid sulfatase (STS). The conversion from DHEAS to DHEA enables this steroid to penetrate the brain. Once inside the brain, a portion of DHEA is again transformed into DHEAS.

DHEAS is the most abundant steroid hormone in the blood (Longcope, 1996). Aside from its role as a precursor of sex steroids, DHEA (as well as DHEAS) is generally recognized as s non-competitive negative allosteric modulators of the GABA-A receptor. In addition, DHEA and DHEAS also act as positive modulators of NMDA and σ-1 receptors (Amato et al., 2010; Baulieu, 1998; Dubrovsky, 2006; Imamura and Prasad, 1998; Majewska, 1992; Paul and Purdy, 1992; Zheng, 2009).

DHEA(S) influences several brain processes, including neuroprotection, stress response, as well as cognitive and mood regulation (Maninger et al., 2009). Several lines of evidence point to DHEA(S) as a strong candidate to account for the male predominance in tic disorders:

• Plasma levels of DHEAS are notably higher in males (Orentreich et al., 1984) offering a possible explanation for the more frequent occurrence of TS in males; furthermore, the increase in testosterone in TS-affected boys is paralleled by a marked augmentation in DHEAS levels (Erbay et al., 2016).

• The typical median age of onset of tics is around 6 years old. This developmental stage coincides with adrenarche, the initial phase of sexual maturation marked by the growth of the zona reticularis in the adrenal cortex. This layer expresses P450c17, enabling the production of DHEA(S) (Endoh et al., 1996). Indeed, the synthesis of this hormone is the key biochemical characteristic of adrenarche. During this stage, the zona reticularis shows a significant decline in the synthesis of 3β-HSD, to reduce the conversion of DHEA into androstenedione and promote its transformation into DHEAS (Dardis et al., 1999; Endoh et al., 1996; Rainey and Nakamura, 2008). From this perspective, the surge in circulating DHEAS levels from adrenarche may help explain the timing of the onset of TS.

• DHEA has marked anabolic functions (Labrie et al., 2006); thus, it is possible that the observed negative effects of these drugs on tic severity may reflect molecular mimicry with DHEA, rather than testosterone.

• The implication of DHEA in TS is also in line with previous observations indicating that flutamide improves tic severity, since this drug has been shown to suppress DHEA(S) synthesis by the adrenal gland (Vrbíková et al., 2004).

Assuming that the role of DHEA(S) in precipitating tic disorders is confirmed, the mechanisms of this action remain elusive. However, it is worth noting that both DHEA and DHEAS act as potent endogenous antagonists of GABA-A receptors, and their effects appear to be complementary. While these two steroids are thought to block GABA-A receptors at different sites of action, DHEAS is more potent than DHEA. As mentioned above, the infusion of GABA-A antagonists produces behaviors strikingly akin to tics in primate and rodent models. Thus, DHEA(S) may trigger the clinical onset of TS in predisposed individuals by antagonizing GABA-A receptors in SPNs and contributing to the formation of aberrant foci in the dorsal striatum.

Contrary to the hypothesis suggesting a significant role of DHEA in tic development, it’s noteworthy that levels of DHEAS, continue to rise peripherally after puberty, a period when tic severity and frequency typically decrease. This inconsistency challenges the direct involvement of DHEAS in tic development, hinting that the increase in DHEAS levels and tic severity between adrenarche and ages 10–12 may merely be correlational. This apparent discrepancy may reflect our incomplete understanding of the metabolic pathways of DHEA and DHEAS in the brain, as well as their developmental trajectory. Specifically, it is uncertain whether the brain’s synthesis and metabolism of these steroids across different developmental stages follow the same mechanisms observed in the adrenal glands and periphery. Thus, the peripheral elevation of DHEAS after puberty may not be reflected by a corresponding increase in brain steroid levels, possibly due to a preference for converting DHEA into androstenedione and testosterone after puberty. A potential divergence between central and peripheral metabolisms of DHEA(S) could potentially explain why tic severity may decrease after puberty despite elevated peripheral DHEAS levels. A comprehensive understanding of these processes, along with age-specific expression patterns of steroid sulfotransferase and steroid sulfatase, could be pivotal in elucidating DHEA’s role in tic progression among individuals aged 6 to 12, as well as the observed reduction in tic severity in boys after puberty.

In addition to this evidence on androgens, preliminary evidence has also pointed to the role of estrogens in tic disorders. Specifically, several anecdotal accounts point to an association between menstrual cycle phases and tic severity in women with TS (Sandyk and Bamford, 1988a; Schwabe and Konkol, 1992). This evidence, as well as a questionnaire-based study (Lees et al., 1984) indicates a premenstrual increase in tics, possibly linked to estrogen level fluctuations. To test this idea, Kompoliti and colleagues (2001) correlated estrogen and progesterone levels with tic measurements throughout a full menstrual cycle in eight women with TS. Although all participants exhibited typical hormonal fluctuations during the menstrual cycle, no correlation was found between hormone levels and tic severity measures. Only one participant reported subjective worsening of tics in the week preceding menstruation, which continued until the onset of menstruation, showing an inverse correlation between tic count and estrogen levels. These results suggest that, while women with tics do not experience menstrual-related fluctuations in tic severity, a subgroup may perceive premenstrual exacerbation of tics associated with estrogen troughs, suggesting a potential protective role of estrogens against tics in these individuals. An alternative explanation may come from a relative increase in progesterone and its metabolite allopregnanolone (Garris and Quigg, 2021, see below). Further investigation is warranted to confirm which female sex steroids may shape tic severity.

THE ROLE OF GLUCOCORTICOIDS AND NEUROSTEROIDS IN TIC DISORDERS

The hypothalamus-pituitary-adrenal (HPA) axis serves as a central regulator of stress responses and is additionally responsible for overseeing various physiological functions, including metabolism, immune response, digestion, emotional regulation, and sexual behavior (Dallman et al., 2000). Stressors trigger the release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Subsequently, CRH is released into the hypophyseal portal circulation via the median eminence and binds to receptors in the anterior pituitary gland, where it prompts the synthesis and release of adrenocorticotropic hormone (ACTH). In turn, this hormone has been shown to trigger the synthesis of different steroids produced by the adrenal cortex by binding to its MC2 receptors (Di Blasio et al., 1990; Hornsby and Gill, 1977; Mahaffee et al., 1974; Ney et al., 1969; Sharma, 1973). Specifically, ACTH promotes the production of cortisol, aldosterone, and DHEA(S) (Arvat et al., 2000; Hornsby et al., 1973; Hung and LeMaire, 1988). As shown in Figure 1, cortisol is produced via the conversion of 17-hydroxyprogesterone into 11-deoxycortisol by 21-hydroxylase (CYP21A2), followed by its conversion into cortisol by 11β-hydroxysteroid type 1 (CYP11B1).

Cortisol orchestrates cardiovascular, metabolic, and immunological changes during stress (Buckingham, 2006; Dhabhar, 2009). Importantly, homeostatic mechanisms are in place to constrain both the magnitude and duration of cortisol’s catabolic effects. The most conspicuous of these mechanisms involves negative feedback regulation by glucocorticoids, which activates glucocorticoid receptors in the hippocampus, hypothalamus, and pituitary, thereby inhibiting further secretion of ACTH and CRH, and ultimately terminating the HPA-axis response to stress (Myers and Ducsay, 2012).

In addition to environmental stressors, the activity of the HPA axis is influenced by the sleep/wake cycle and follows a circadian pattern (Backhaus et al., 2004), with the lowest levels of cortisol in the middle of the night. Furthermore, the release of CRH is triggered by threatening contextual factors and is negatively regulated by circulating cortisol levels (Stetler and Miller, 2011).

As mentioned above, several investigations have shown that physical and emotional stress levels can have detrimental effects on tic severity and related symptoms (Bornstein et al., 1990; Conelea and Woods, 2008; Lombroso et al., 1991; Nelson, 1993; Shapiro et al., 1988). However, the role of stress remains controversial since one of the most commonly used procedures to induce psychosocial stress in the laboratory, the Trier stress test, was not conducive to exacerbating tics (Buse et al., 2016).

Preliminary findings suggest that individuals with TS may demonstrate atypical reactions to physical stress, including exposure to thermal stress (Bornstein et al., 1990; Scahill et al., 2001). More extensive research has delved into the influence of emotional contexts on stress responses in TS patients. In particular, a few early studies suggested that emotionally traumatic experiences may precede tic onset (Carney, 1977; Surwillo et al., 1978). In a longitudinal study conducted by Lin et al. (2007), researchers aimed to investigate the short-term effects of life stressors on the severity of tics and related symptoms. The study included 45 children and adolescents diagnosed with TS and/or OCD, as well as 41 healthy subjects. Over the course of 2 years, the severity of participants’ tics, obsessive-compulsive and depressive symptoms were rated. Results from the study indicated that TS and/or OCD patients faced more psychosocial stress than the healthy subjects. However, the impact of negative life events was greater on future depressive symptoms than tic and/or OCD severity. Importantly, current levels of psychosocial stress and depression had independent predictive value for future tic severity, whereas current tic severity did not predict psychosocial stress or depressive symptoms (Lin et al., 2007). Other triggers have been considered as potential factors for exacerbation of stress, including sleep deprivation, fatigue, boredom, and extreme anxiety (Godar and Bortolato, 2017). These findings underscore the importance of considering the influence of life stressors on tic severity in clinical practice.

In contrast with the ample evidence of the detrimental effects of stress on tic severity, the role of the HPA axis in tic disorders has surprisingly been investigated only by a few studies. One of the earliest observations suggested an altered reactivity of the HPA axis in TS patients (Sandyk and Bamford, 1988b). In this study, the administration of naloxone, an opioid antagonist, induced a significant increase in cortisol levels in TS patients. Further research bolstered this concept, revealing that TS individuals often experience more pronounced increases in HPA hormone levels in stressful conditions.

Chappell and colleagues (1994) investigated how lumbar puncture stress influences plasma ACTH and cortisol levels, urinary catecholamines, and both self-assessed and clinician-evaluated anxiety in 13 medication-free TS patients and 10 controls. Hormone levels were monitored at various time intervals throughout the day, both before and after the lumbar puncture procedure. Both groups exhibited peak plasma cortisol levels immediately after the procedure. However, the TS group showed significantly higher levels, average, and peak of ACTH than the control group. Notably, in a subsequent study with 21 TS-affected individuals, 20 subjects with OCD, and 29 healthy controls, TS patients were found to exhibit greater CRH levels in CSF (Chappell et al., 1996).

Corbett and colleagues (2008) tested salivary cortisol levels and their circadian rhythmicity in a total of 20 unmedicated TS children (17 males and 3 females aged between 7 and 13 years) and 16 age-matched healthy control subjects (11 males and 5 females). No significant differences were detected in the physiological circadian cortisol patterns between the two groups; however, lower evening cortisol values were detected in the TS group, which negatively correlated with tic severity. In addition, the authors investigated the acute stress response, utilizing a simulated and actual MRI as stress-inducing stimuli. Cortisol responses were notably higher in the TS group irrespective of the stressor (simulated or actual MRI). The study meticulously accounted for potential confounding factors stemming from clinical and demographic variables.

Notably, HPA activity seems to be dysregulated also in other TS comorbid disorders, such as OCD and ADHD. OCD patients exhibit higher cortisol secretion levels in comparison to age-matched healthy individuals (Brambilla et al., 2000; Kluge et al., 2007; Monteleone et al., 1994). However, cortisol levels did not correlate with symptom severity and studies on acute stressors have yielded inconsistent findings in OCD patients (Altemus et al., 1992; Chappell et al., 1996; Gustafsson et al., 2008). Contradictive findings were also identified in ADHD patients. While some authors have shown disrupted circadian rhythms (Baird et al., 2012; Kaneko et al., 1993), others have failed to find similar alterations in HPA activity (Hirvikoski et al., 2009; Pesonen et al., 2011).

Taken together, these data suggest that TS patients exhibit a dysregulated HPA axis; however, the underlying mechanisms remain elusive. One of the factors that may lead to dysregulations of the HPA axis is DHEA(S). This steroid is co-released with cortisol in response to ACTH (Hornsby, 1995; Parker and Odell, 1980), but is widely recognized for its anti-glucocorticoid effects (Browne et al., 1992; Kalimi et al., 1994). One of the possible mechanisms whereby DHEA may oppose cortisol is by inhibiting the enzymes responsible for converting cortisol’s inactive metabolite cortisone back into cortisol (Hennebert et al., 2007; Maninger et al., 2009). Acute stress has been shown to significantly increase DHEA and DHEAS concentrations by 60–75% (Izawa et al., 2008; Lennartsson et al., 2012; Marceau et al., 2012). The coordinated release of DHEA with cortisol in response to acute stress is believed to protect against the potential adverse effects of excessive cortisol activity (Maninger et al., 2009) and is associated with reduced negative affect in response to stress (Izawa et al., 2008). From this perspective, several authors have proposed that analyzing cortisol/DHEA or cortisol/DHEAS ratios, rather than simply cortisol surges, may serve as better indicators of allostatic load and stress response (McEwen, 1998; Sapolsky et al., 1986; Wolkowitz et al., 2001). Future studies are needed to verify whether changes in DHEA(S) concentrations may accompany the observed circadian changes in cortisol activity in TS. Alternatively, the abnormalities of the HPA axis in TS and other tic disorders may reflect other yet unknown alterations. For example, other neuroactive steroids play a critical role in governing the function of the HPA axis. Most evidence indicates that GABA regulates the activity of the HPA axis (Cullinan et al., 2008; Decavel and Van den Pol, 1990; Jones et al., 1984), particularly through its GABA-A receptors (Brickley and Mody, 2012). Two of the most potent positive modulators of this receptor are allopregnanolone and THDOC, two 3α, 5α-reduced neurosteroids (Morrow et al., 1987). Both steroids bind to allosteric sites, which are distinct from the receptor’s active site. This action increases the probability of GABA binding to the active site, subsequently enhancing chloride channel opening and membrane currents (Belelli and Lambert, 2005; Chisari et al., 2010). This allosteric modulation is responsible for anxiolytic, anti-conflict, and analgesic effects (Bitran et al., 1995; Engin and Treit, 2007; Frye and Rhodes, 2006; Kavaliers and Wiebe, 1987; Pibiri et al., 2006; Pinna et al., 2003), all of which align with an integrated and adaptive response to stress (Purdy et al., 1991). Furthermore, these neuroactive steroids regulate the HPA-axis through the modulation of GABA-A receptors and the following alterations in GABAergic neurotransmission (Belelli and Lambert, 2005; Morrow et al., 1995).

Research conducted in animal models consistently demonstrates that neurosteroids and HPA axis are functionally linked. In particular, several studies in rodents have shown that acute stress leads to the rapid production of allopregnanolone and THDOC. The relationship between neurosteroids and HPA axis, however, is relatively complex. On the one hand, Sarkar and colleagues (2011) showed that THDOC is a key regulator of the HPA axis through positive feedback on CRH neurons in the PVN under stress conditions.

On the other hand, treatment of rats with these steroids attenuates stress-induced increases in plasma ACTH and cortisol (Owens et al., 1992; Patchev et al., 1996). These findings suggest that peripheral neurosteroids are key in shaping the homeostasis of HPA axis. The role of allopregnanolone in the regulation of the HPA axis, however, has been studied only marginally. Droogleever Fortuyn and colleagues (2004) observed in a predominantly male sample that allopregnanolone and cortisol increased significantly during an acute stressor, and levels of these steroids were positively correlated. Similarly, Girdler and colleagues (2001) found increases in allopregnanolone after a few minutes after stress onset.

The production of allopregnanolone and THDOC is under the control of 5α-reductase (5αR), as it catalyzes the key rate-limiting step in their synthesis. Specifically, 5αR is responsible for saturating the 4,5 double bond in the A ring of Δ4–3-ketosteroid substrates, such as deoxycorticosterone, progesterone, androstenedione, and testosterone. The activity of 5αR is crucial as it enables the irreversible transformation of these compounds into their respective metabolites, for instance, it facilitates the conversion of testosterone into dihydrotestosterone (DHT) (Paba et al., 2011).

Thus, building on the findings by Peterson et al. (1998) on the beneficial effects of flutamide (as reported above), we tested whether finasteride, the prototypical 5αR inhibitor, may lead to similar results, by blocking DHT synthesis and the subsequent androgen signaling. This hypothesis was tested with a 34-year-old male TS patient who hadn’t benefited from conventional antipsychotic treatments. The patient displayed severe vocal tics, including coprolalic utterances, and self-harming motor tics. The dosage of 5 mg/day of finasteride resulted in a gradual but noticeable reduction in both motor and vocal tics, as assessed by the Yale Global Tic Severity Scale (YGTSS), without any noticeable adverse effects. This was a significant improvement compared to previous antipsychotic treatments, which had only given short-term relief and were often discontinued due to severe extrapyramidal and cognitive side effects. Notably, when finasteride treatment was stopped after eighteen weeks, the patient’s symptoms significantly intensified. However, reintroducing the 5αR inhibitor led to improved symptoms once again (Bortolato et al., 2007).

The potential of finasteride as an additional treatment option for TS was further supported by an initial open-label study involving ten adult male patients. Participants showed a marked decrease in the severity of their tics and related compulsive behaviors (though not in obsessive symptoms) within an eighteen-week period after starting finasteride treatment (Muroni et al., 2011). A subsequent study of 16 patients, confirmed the beneficial effects of finasteride, showing significant improvement in symptoms over 24 weeks (Bortolato et al., 2013). Additionally, a study conducted in Taiwan echoed these positive findings (Wang, 2014).

However, the prospect of using finasteride as a treatment for TS encounters various obstacles: (i) its effects that can reduce masculine characteristics restrict its use to adult patients; (ii) recent studies have raised concerns about the risk of depression and sexual dysfunction in some individuals undergoing finasteride treatment (Rahimi-Ardabili et al., 2006; Traish et al., 2015). In response to these challenges, there has been a shift in focus towards comprehending the mechanisms behind finasteride’s action and seeking alternative therapeutic options. These alternatives aim to replicate the beneficial aspects of finasteride but with a more favorable safety profile.

Thus, our research focused on the effects of this drug in rodent models to better delineate the possible mechanisms of action and identify new druggable targets. Our initial preclinical investigations into the therapeutic potential of finasteride and other 5α-reductase inhibitors, such as dutasteride, involved studying their impacts on rats treated with dopaminergic agonists like amphetamine and apomorphine. These agonists are known to trigger stereotyped behaviors and sensorimotor gating (PPI) deficits, which are valuable for preclinical evaluations of new drugs’ effectiveness in reducing tic severity (Godar et al., 2014) and provide a critical measure for assessing information-processing challenges in these individuals (Swerdlow and Sutherland, 2006).

Our research showed that both finasteride and dutasteride effectively decreased the stereotypical behaviors and the PPI deficits caused by dopaminergic agonists in rats. These effects were similar to those of antipsychotic medications. However, a key difference was that the 5α-reductase inhibitors, unlike antipsychotic drugs, did not produce overt extrapyramidal side effects (Bortolato et al., 2008). Capitalizing on these results, we first tested the local effects of finasteride in different brain areas and found that infusion of this drug in the PFC and in the shell of the nucleus accumbens reversed the PPI deficits produced by dopamine receptor agonists (Devoto et al., 2012). Notably, subsequent studies indicated that the effects of finasteride were directly related to the downstream effects of D1, but not D2, receptors in mice and rats (Frau et al., 2016, 2013).

We then discovered that sleep deprivation, a condition often reported to exacerbate tics, increases the expression of 5αR isoenzymes (Frau et al., 2016). Notably, while sleep deprivation leads to PPI deficits, these outcomes were suppressed by finasteride and worsened by allopregnanolone administration (Frau et al., 2013). Given that allopregnanolone is a critical neurosteroid for the reaction to short-term stress (Purdy et al., 1992), we later tested the hypothesis that other acute stressors may lead to PPI deficits via increased AP levels. Indeed, we found that AP dose-dependently reduces PPI in rodents and that several stressors reduce PPI by increasing AP levels in the PFC (Cadeddu et al., 2022). Notably, we also found that AP is necessary and sufficient to enable the PPI-disruptive properties of D1 receptor agonists (Frau et al., 2023; Mosher et al., 2019). Building on these premises, we also showed that AP mediates the exacerbation of tic-like manifestations in D1CT-7 and CIN-d mice (Cadeddu et al., 2023b; Mosher et al., 2017).

Emerging evidence suggests that stress may adversely affect the capacity to suppress tics (Conelea et al., 2011). Several electroencephalography (EEG) and imaging studies have identified that tic suppression is orchestrated by the frontal and prefrontal cortex (Ganos et al., 2014; Hong et al., 2013; Serrien et al., 2005; van der Salm et al., 2018). The mechanism of AP may be based on the activation of GABA-A receptors in the PFC. While the precise mechanism still requires more investigation, a recent study found that the negative effects of stress and AP in D1CT-7 and CIN-d mice were mitigated by isoallopregnanolone (isoAP), which is the natural 3β-epimer of AP (Cadeddu et al., 2023b, 2020). IsoAP functions as a natural antagonist to AP, counteracting its effects on GABA-A receptors. Significantly, this compound has a strong safety profile and has shown good tolerability in previous Phase IIb clinical trials, as reported by Bixo et al. (2017). Expanding upon these encouraging preclinical findings, a randomized, multicenter, phase IIa open-label clinical trial was recently conducted in Denmark. This trial aimed to assess the safety and effectiveness of isoAP (sepranolone) in TS patients (EudraCT: 2021-001045-12). As expected, sepranolone was very well tolerated by patients, and the only reported adverse event was represented by skin irritation around the injection site. The results of this trial showed a reduction of 4 points in total tic severity (YGTSS) vs. patients treated with standard care. Due to a large variance of effects within the group treated with sepranolone, this effect only reached marginal significance (P=0.051). These results indicate that sepranolone may be an effective therapy in a subgroup of patients, likely characterized by high responsiveness to stress.

CONCLUSIONS

The evidence presented in this review shows how the study of neuroactive steroids, particularly allopregnanolone and dehydroepiandrosterone (DHEA), may provide valuable insights into the neurobiological mechanisms of tic disorders and help understand both the sex differences and the stress sensitivity in TS. As noted above, several details of how these steroids may influence CSTC activity remain unknown, and data on the levels of these steroids in TS-affected children remain marginal.

Our group is currently involved in the ReConNECT (Research Consortium on NeuroEndocrine Causes of Tics) study, based at the University of Utah and the University of Miami, which is undertaking the first comprehensive investigations on the steroidomic profile in urine and saliva in children affected by chronic tic disorders and TS.

While more research is needed to fully elucidate the mechanisms by which neuroactive steroids impact tic disorders, the growing body of evidence underscores their significance in the pathophysiology of these conditions. As we continue to uncover the intricate neurobiology underlying TS and tic disorders, the development of targeted therapies involving steroids holds the potential to enhance the quality of life for individuals affected by these challenging conditions. This evolving field offers hope for more effective interventions and improved outcomes in the management of tic disorders. Of particular interest are GABA-A receptor modulators that may impinge on the same sites of action as allopregnanolone and DHEA to reduce fluctuations and improve other therapies. In particular, given the importance of stress reduction in CBIT, we envision allopregnanolone antagonists (such as isoallopregnanolone) may synergize with this therapy to improve compliance and overall effectiveness of behavioral interventions.