Antidepressant-induced Paradoxical Anxiety, Akathisia, and Complex Vocal Tics in a Patient with Panic Disorder and Crohn's Disease: A Case Report.

BACKGROUND: Antidepressant-induced paradoxical anxiety is a fairly common phenomenon seen in patients who are initiated on antidepressants. However, akathisia is a very uncommon manifestation of antidepressants. Much more rarely, antidepressants are also associated with the emergence of motor and vocal tics. This case adds to the growing literature of rare adverse events induced by antidepressants and aims to stimulate future research into the mechanism and risk factors of this phenomenon. CASE PRESENTATION: In this case report, we describe a patient with panic disorder and co-morbid Crohn's disease who developed worsening anxiety, akathisia and vocal tics upon initiation of fluvoxamine. This is the first case report to describe the emergence of both akathisia and vocal tics in the same patient following antidepressant initiation. After discontinuation of fluvoxamine, the patient's symptoms resolved. CONCLUSION: Antidepressant-induced akathisia and tics are often distressing both to the patient and their loved ones, and can be very puzzling to the clinician. It is important for clinicians to recognise that, although rare, antidepressants can adverse effects. When these symptoms arise, it should prompt immediate discontinuation of the offending antidepressant.

Efficacy of clonidine in the treatment of children with tic disorder co-morbid with attention deficit hyperactivity disorder.

OBJECTIVE: The current research was designed to assess the efficacy of clonidine in the treatment of children with tic disorder co-morbid with attention deficit hyperactivity disorder. PATIENTS AND METHODS: A total of 154 children with tic disorder co-morbid with attention deficit hyperactivity disorder admitted to our hospital from July 2019 to July 2022 were recruited and assigned to receive either methylphenidate hydrochloride plus haloperidol (observation group) or clonidine (experimental group), with 77 cases in each group. Outcome measures included clinical efficacy, Yale Global Tic Severity Scale (YGTSS) scores, Conners Parent Symptom Questionnaire (PSQ) scores, and adverse events. RESULTS: Clonidine was associated with markedly higher clinical efficacy vs. methylphenidate hydrochloride plus haloperidol (p<0.05). Clonidine offered more significant mitigation of the tic disorder vs. methylphenidate hydrochloride plus haloperidol, as evinced by the lower kinetic tic scores, vocal tic scores, and total scores (p<0.05). Children exhibited markedly milder tic symptoms after clonidine monotherapy vs. those with dual therapy of methylphenidate hydrochloride and haloperidol, suggested by the lower scores of character problems, learning problems, psychosomatic disorders, hyperactivity/impulsivity, anxiety index, and hyperactivity index (p<0.05). Clonidine features a higher safety profile than methylphenidate hydrochloride plus haloperidol by reducing the incidence of adverse events (p<0.05). CONCLUSIONS: Clonidine effectively alleviates tic symptoms, reduces attention deficit and hyperactivity/impulsivity in children with tic disorder co-morbid attention deficit hyperactivity disorder, and features a high safety profile.

Ecopipam for Tourette Syndrome: A Randomized Trial.

BACKGROUND AND OBJECTIVES: All US Food and Drug Administration-approved medications for Tourette syndrome are antipsychotics, and their use is limited by the risk of weight gain, metabolic changes, and drug-induced movement disorders. Several small trials suggest that ecopipam, a first-in-class, selective dopamine 1 receptor antagonist, reduces tics with a low risk for these adverse events. This trial sought to further evaluate the efficacy, safety, and tolerability of ecopipam in children and adolescents with moderate to severe Tourette syndrome. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, phase 2b trial. Subjects aged ≥6 to <18 years with a baseline Yale Global Tic Severity Score Total Tic Score of ≥20 were randomly assigned 1:1 to ecopipam (n = 76) or placebo (n = 77). The primary endpoint was mean change over 12 weeks in the Yale Global Tic Severity Score Total Tic Score. The Clinical Global Impression of Tourette Syndrome Severity was the secondary endpoint. Safety and tolerability were evaluated at each study visit. RESULTS: Total tic scores were significantly reduced from baseline to 12 weeks in the ecopipam group compared with placebo (least squares mean differences -3.44, 95% confidence interval -6.09 to -0.79, P = .01). Improvement in Clinical Global Impression of Tourette Syndrome Severity was also greater in the ecopipam group (P = .03). More weight gain was seen in subjects assigned to placebo. No metabolic or electrocardiogram changes were identified. Headache (15.8%), insomnia (14.5%), fatigue (7.9%), and somnolence (7.9%) were the most common adverse events. CONCLUSIONS: Among children and adolescents with TS, ecopipam reduces tics to a greater extent than placebo, without observable evidence of common antipsychotic-associated side effects.

Sertraline-Induced Tics: A Case Report and Narrative Review.

This brief report describes the case of a 16-year-old girl who was commenced on sertraline for anxiety and depression, and subsequently developed severe and debilitating motor tics. Cessation of sertraline was associated with the resolution of tics; after this, paroxetine was trialled and well tolerated with good response of targeted symptoms and without re-emergence of tics. A narrative literature review yielded a retrospective observational study and eight single case reports on selective serotonin receptor inhibitor-induced motor tics (three in adolescents and five in adults). Tics are not commonly considered as a side-effect of SSRIs. This case report is novel is several aspects: the tics emergence was immediate whereas previous cases were delayed; the tics symptoms were measured and quantified by a validated scale; a dose-response relationship was observed; to our knowledge, our case was the first adolescent female reported; and finally, paroxetine was well-tolerated as a substitute, although it is unclear whether the observed tics-sparing effect is co-incidental, ideocratic or can be replicated.

Tetrahydrocannabinol and Cannabidiol in Tourette Syndrome.

BACKGROUND: Tourette syndrome is characterized by chronic motor and vocal tics. There is preliminary evidence of benefit from cannabis products containing Δ9-tetrahydrocannabinol (THC) and that coadministration of cannabidiol (CBD) improves the side-effect profile and safety. METHODS: In this double-blind, crossover trial, participants with severe Tourette syndrome were randomly assigned to a 6-week treatment period with escalating doses of an oral oil containing 5 mg/ml of THC and 5 mg/ml of CBD, followed by a 6-week course of placebo, or vice versa, separated by a 4-week washout period. The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range, 0 to 50 [higher scores indicate greater severity of symptoms]). Secondary outcomes included video-based assessment of tics, global impairment, anxiety, depression, and obsessive-compulsive symptoms. Outcomes were correlated with plasma levels of cannabinoid metabolites. A computerized cognitive battery was administered at the beginning and the end of each treatment period. RESULTS: Overall, 22 participants (eight female participants) were enrolled. Reduction in total tic score (at week 6 relative to baseline) as measured by the YGTSS was 8.9 (±7.6) in the active group and 2.5 (±8.5) in the placebo group. In a linear mixed-effects model, there was a significant interaction of treatment (active/placebo) and visit number on tic score (coefficient = −2.28; 95% confidence interval, −3.96 to −0.60; P=0.008), indicating a greater decrease (improvement) in tics under active treatment. There was a correlation between plasma 11-carboxy-tetrahydrocannabinol levels and the primary outcome, which was attenuated after exclusion of an outlier. The most common adverse effect in the placebo period was headache (n=7); in the active treatment period, it was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration (n=8). CONCLUSIONS: In severe Tourette syndrome, treatment with THC and CBD reduced tics and may reduce impairment due to tics, anxiety, and obsessive-compulsive disorder; although in some participants this was associated with slowed mentation, memory lapses, and poor concentration. (Funded by the Wesley Medical Research Institute, Brisbane, and the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically-funded research organization at the University of Sydney, Australia; Australian and New Zealand Clinical Trials Registry number, ACTRN12618000545268.)

The Recurrence of Motor Tics Mediated by Oral Prednisolone Use in Autistic Children: A Case Report.

OBJECTIVES: This study aimed to report motor tics worsening by prednisolone acute treatment, despite the use of aripiprazole and clonidine. It was also aimed to discuss the mechanisms involved in neuropsychiatric adverse effects with the use of corticosteroids. METHODS: It was reported a 7-year-old boy patient with a history of autism spectrum disorder and motor tics. He has remitted motor tics with an association between aripiprazole and clonidine. However, was registered motor tics' recurrence with acute use of prednisolone. CONCLUSIONS: The neuropsychiatric adverse effects mediated by corticosteroid use are low explored, mainly in pediatric clinical practice. The prednisolone prescription is widespread in childhood and, considering some vulnerable conditions to this type of adverse effects, is imperative.

Drug-induced tics: An observational postmarketing study.

OBJECTIVES: While drug-induced tics have been described, in particular with neuroleptics, psychostimulants, or anti-epileptics, the strength and the direction of these associations are still debated. The aim of this study was to investigate the association between tics and drug exposure through a two-step analysis in two pharmacovigilance databases. METHODS: We first performed a descriptive clinical analysis of cases registered in the French pharmacovigilance database (FPVD) from January 1985 to December 2018. We then performed a disproportionality analysis in VigiBase®, the WHO pharmacovigilance database, from January 1967 to June 2019, through the calculation of reporting odds ratio (ROR). RESULTS: The drugs most frequently associated with tics in the FPVD were methylphenidate, lamotrigine, montelukast, tramadol, mirtazapine, venlafaxine, aripiprazole, and risperidone. In VigiBase®, we found a significant ROR with methylphenidate (ROR 37.54, 95% confidence interval [CI] 34.81-40.48), montelukast (ROR 12.18, 95% CI 10.29-14.41), aripiprazole (ROR 7.40, 95% CI 6.35-8.62), risperidone (ROR 4.40, 95% CI 3.72-5.21), and venlafaxine (ROR 1.52, 95% CI 1.14-2.03). CONCLUSION: This postmarketing study confirmed a potential harmful association with methylphenidate (the highest association, as expected), aripiprazole, risperidone, lamotrigine, and venlafaxine and, interestingly, found a strong signal with montelukast, which, to our knowledge, had never been published before.

Lactobacillus plantarum PS128 ameliorates 2,5-Dimethoxy-4-iodoamphetamine-induced tic-like behaviors via its influences on the microbiota-gut-brain-axis.

We previously reported a novel psychobiotic strain of Lactobacillus plantarum PS128 (PS128) which could ameliorate anxiety-like& depression-like behaviors and modulate cerebral dopamine (DA) and serotonin (5-HT) in mice. Here, we examine the possibility of using PS128 administration to improve tic-like behaviors by using a 5-HT2A and 5-HT2C receptor agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI). PS128 was orally administered to male Wistar rat for 2 weeks before two daily DOI injections. We recorded the behaviors immediately after the second DOI injection and compared the results with control and haloperidol treatment groups. PS128 significantly reduced tic-like behaviors and pre-pulse inhibition deficit in a threshold-dose of 109 CFU per day. Brain tissue analysis showed that DOI induced abnormal DA efflux in the striatum and prefrontal cortex, while PS128 ingestion improved DA metabolism and increased norepinephrine (NE) levels in these two regions. In addition, PS128 ingestion increased DA transporter and ß-arrestin expressions and decreased DOI-induced phosphorylation of DA and cAMP regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) at Thr34 and extracellular regulated protein kinases (ERK). PS128 ingestion also modulated peripheral 5-HT levels and shaped the cecal microbiota composition, which helps to alleviate DOI-induced dysbiosis. These results suggested that PS128 ameliorated DOI-induced tic-like hyper-active behaviors via stabilizing cerebral dopaminergic pathways through its modulation of host's microbiota-gut-brain axis. Thus, we believe there are potentials for utilizing psychobiotics to improve syndromes caused by DA dysregulation in DA-related neurological disorders and movement disorders such as Tourette syndrome.

[Side effects of methylphenidate in children and the young]. / Efectos secundarios del metilfenidato en poblacion infantil y juvenil.

INTRODUCTION: The use of psychostimulants has been present in common medical practice since the 20th century and has undergone an exponential growth in terms of the number of prescriptions. AIM: To review the current state of knowledge about the side effects of psychostimulants in the child and teen populations. DEVELOPMENT: A review was performed by searching in different databases and included clinical analyses, observational prospective studies and systematic reviews. A minimum increase in blood pressure and heart rate are observed, but some studies highlight an underestimation of the long-term risk. As regards appetite and growth, almost all the current literature points to a slowing of the rate of growth, which is regained on interrupting treatment. One important factor, as is the parallel evolution of bone age, has not been evaluated in most of the studies carried out to date. No significant worsening of sleep was noted in patients treated with psychostimulants with respect to those who are not being treated. With regard to the central nervous system, there does not seem to be any evidence of an increased risk of the appearance or exacerbation of tics following introduction of the treatment. Affect and emotion are areas that have been barely explored. CONCLUSIONS: It is important to have more evidence on the safety of these drugs. It is therefore essential to have access to studies that cover a period of time consistent with the duration of these treatments.

TITLE: Efectos secundarios del metilfenidato en poblacion infantil y juvenil.Introduccion. El uso de farmacos psicoestimulantes esta presente en la practica medica habitual desde principios del siglo XX y ha experimentado un incremento exponencial en cuanto a prescripciones. Objetivo. Revisar el estado de conocimiento actual sobre los efectos secundarios de los psicoestimulantes en poblacion infantil y juvenil. Desarrollo. Se realiza una revision tras consultar diferentes bases de datos, incluyendo en esta revision analisis clinicos, metaanalisis, estudios prospectivos observacionales y revisiones sistematicas. Se observa un incremento minimo en la tension arterial y la frecuencia cardiaca, pero algunos estudios recientes apuntan a una infraestimacion del riesgo a largo plazo. En lo que se refiere al apetito y el crecimiento, casi toda la bibliografia actual apunta a una ralentizacion del ritmo de crecimiento, que se recupera al interrumpir el tratamiento. Un factor importante, como es la evolucion en paralelo de la edad osea, no se ha valorado en la mayoria de los estudios realizados. En el sueño no habria empeoramiento significativo en los pacientes tratados con psicoestimulantes respecto a los no tratados. En relacion con el sistema nervioso central, no parece haber evidencia de un incremento del riesgo de aparicion o empeoramiento de tics tras introducir el tratamiento. El afecto y la emocion son areas poco exploradas. Conclusiones. Es importante tener una mayor evidencia de la seguridad de estos farmacos. Para ello es imprescindible poder disponer de estudios de una extension en el tiempo consecuente con la duracion de estos tratamientos.

Acute Worsening of Tics on Varenicline.

OBJECTIVE: The aim of this study was to report worsening of Tourette syndrome (TS) in 2 patients treated with varenicline. BACKGROUND: Abnormal dopaminergic signaling is likely involved in the pathophysiology of TS. Varenicline is a partial α4ß2 nicotinic acetylcholine agonist that enhances dopamine release. Therefore, the use of varenicline may influence tics in patients with TS. METHOD: We analyzed and described 2 case studies on patients with significant worsening of tics after treatment with varenicline. RESULTS: Patient 1 had motor tics in childhood, which completely resolved by the age of 20 years. At the age of 25 years, he started varenicline and stopped smoking. Within 2 weeks, he developed motor followed by vocal tics that persisted despite stopping varenicline and restarting smoking. The tics were complex, medically refractory, and caused severe disability at work and school (Yale Global Tic Severity Scale score, 86). Patient 2 developed motor and vocal tics in adolescence that persisted into her 20s and caused significant disability in association with psychiatric comorbidities. At the age of 31 years, she started varenicline to quit smoking, which led to a marked increase in tic frequency and severity. Varenicline was discontinued after 3 weeks with improvement to baseline tic severity (Yale Global Tic Severity Scale score, 94). Ultimately, both patients successfully underwent deep brain stimulation to bilateral centromedian/parafascicular complex thalamic nuclei for medically refractory TS. CONCLUSIONS: We report 2 patients with motor and/or vocal tics that had severe worsening of tics after varenicline use. This may be due to varenicline-induced increased striatal dopamine in conjunction with nicotine cessation, influencing dopamine receptor sensitivity in TS. Providers should be cautious in prescribing varenicline to patients with TS.

Lamotrigine Induced Whole Body Tics: A Case Report and Literature Review.

Lamotrigine is an anticonvulsant medication that also has utility in the treatment of bipolar disorder. It has been associated with many side effects, including rashes that can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. It has also been associated with the development of motor tics, most commonly in the head, neck, and shoulders. We will now present the case of a 45-year-old woman who developed tics that involved the entire left side of her body after her dose of lamotrigine was increased from 200 mg daily (2.0 mg/kg/day) to 225 mg daily (2.3 mg/kg/day). We will review the prior cases of lamotrigine induced tics, and compare them to the circumstances surrounding our patient. We will also discuss the neurobiology of tics and make suggestions to improve the tics, based on the reported cases.

Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. RESULTS: There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). CONCLUSIONS: The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting.

Corticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition.

The pathophysiology of the tics that define Gilles de la Tourette syndrome (TS) is not well understood. Local disinhibition within the striatum has been hypothesized to play a pathogenic role. In support of this, experimental disinhibition by local antagonism of GABA-A receptors within the striatum produces tic-like phenomenology in monkey and rat. We replicated this effect in mice via local picrotoxin infusion into the dorsal striatum. Infusion of picrotoxin into sensorimotor cortex produced similar movements, accompanied by signs of behavioral activation; higher-dose picrotoxin in the cortex produced seizures. Striatal inhibition with local muscimol completely abolished tic-like movements after either striatal or cortical picrotoxin, confirming their dependence on the striatal circuitry; in contrast, cortical muscimol attenuated but did not abolish movements produced by striatal picrotoxin. Striatal glutamate blockade eliminated tic-like movements after striatal picrotoxin, indicating that glutamatergic afferents are critical for their generation. These studies replicate and extend previous work in monkey and rat, providing additional validation for the local disinhibition model of tic generation. Our results reveal a key role for corticostriatal glutamatergic afferents in the generation of tic-like movements in this model.

Bupropion XL-induced motor and vocal tics.

Tics are stereotypical repetitive involuntary movements (motor tics) or sounds (vocal tics). Although the emergence of tics were reported in a few cases with the use of selective serotonin reuptake inhibitors, there was no case with bupropion extended-release (Bupropion XL). The current case report presents a male patient developing motor and vocal tics with the use of bupropion XL.

A behavioural test battery to investigate tic-like symptoms, stereotypies, attentional capabilities, and spontaneous locomotion in different mouse strains.

The preclinical study of human disorders associated with comorbidities and for which the aetiology is still unclear may substantially benefit from multi-strain studies conducted in mice. The latter can help isolating experimental populations (strains) exhibiting distinct facets in the parameters isomorphic to the symptoms of a given disorder. Through a reverse-translation approach, multi-strain studies can inform both natural predisposing factors and environmental modulators. Thus, mouse strains selected for a particular trait may be leveraged to generate hypothesis-driven studies aimed at clarifying the potential role played by the environment in modulating the exhibition of the symptoms of interest. Tourette's syndrome (TS) constitutes a paradigmatic example whereby: it is characterized by a core symptom (tics) often associated with comorbidities (attention-deficit-hyperactivity and obsessive-compulsive symptoms); it has a clear genetic origin though specific genes are, as yet, unidentified; its course (exacerbations and remissions) is under the influence of environmental factors. Based on these considerations, we tested four mouse strains (ABH, C57, CD1, and SJL) - varying along a plethora of behavioural, neurochemical, and immunological parameters - on a test battery tailored to address the following domains: tics (through the i.p. administration of the selective 5-HT2 receptor agonist DOI, 5mg/kg); locomotion (spontaneous locomotion in the home-cage); perseverative responding in an attentional set shifting task; and behavioural stereotypies in response to a single amphetamine (10mg/kg, i.p.) injection. Present data demonstrate that while ABH and SJL mice respectively exhibit selective increments in amphetamine-induced sniffing behaviour and DOI-induced tic-like behaviours, C57 and CD1 mice show a distinct phenotype, compared to other strains, in several parameters.

Paliperidone-associated motor tics.

OBJECTIVES: Paliperidone-associated motor tics. METHOD: Case report. RESULTS: We report a 30-year-old man with schizophrenia who developed motor tics (eye blinking) after treatment of paliperidone up to 15 mg daily. CONCLUSION: Tic-like symptoms, from simple eye blinking to complex Tourette-like syndrome, may occur during paliperidone treatment, especially with high dose.

Antidepressant-like effects of a water-soluble extract from the culture medium of Ganoderma lucidum mycelia in rats.

BACKGROUND: Ganoderma lucidum is a popular medicinal mushroom used for promoting health and longevity in Asian countries. Previously, we reported that a water-soluble extract from a culture medium of Ganoderma lucidum mycelia (MAK) exerts antioxidative and cerebroprotective effects against ischemia-reperfusion injury in vivo. Here, we evaluated the antidepressant and anxiolytic activities of MAK in rats. METHODS: MAK (0.3 or 1 g/kg, p.o.) was administered in the experimental animals 60 min before the forced swimming, open-field, elevated plus-maze, contextual fear-conditioning, and head twitch tests. Additionally, the mechanisms involved in the antidepressant-like action of MAK were investigated by the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP)- or 5-HT2A agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced head twitch responses. RESULTS: Treatment with MAK (1 g/kg) exhibited antidepressant-like effects in the forced swimming test, attenuated freezing behavior in the contextual fear-conditioning test, and decreased the number of head twitches induced by DOI, but not with 5-HTP. No significant response was observed in locomotion or anxiety-like behavior, when the animals were evaluated in the open-field or elevated plus-maze test, respectively. CONCLUSIONS: These data suggest that MAK has antidepressant-like potential, which is most likely due to the antagonism of 5-HT2A receptors, and possesses anxiolytic-like effects toward memory-dependent and/or stress-induced anxiety in rats.