Status dystonicus is characterised by involuntary sustained or intermittent muscle contractions of muscles causing repetitive twisting movements, abnormal postures of the body, or both is a rare but life-threatening movement disorder. Early diagnosis and management of status dystonicus prevent serious complications. We report a 2 years old previously developmental delay diagnosed girl who presented with generalised contractions of the whole body. Tightening of limbs is aggravated by touching her backside which is a very unique feature. Dystonia is associated with severe sweating and was confused with a seizure event. The patient was treated with midazolam, clonidine, phenytoin, gabapentin, pyridoxine, baclofen, and trihexyphenidyl. She was admitted to the intensive care unit for monitoring. The patient partially recovered after 10 days of treatment.

Trihexyphenidyl works as an anticholinergic and is used for the treatment of tremors, spasms, stiffness, and weak muscle control seen in patients with Parkinson disease. It can also be used for the prevention or treatment of similar muscular conditions, which are caused by certain central nervous system (CNS) drugs such as fluphenazine, haloperidol, chlorpromazine. It was approved for the management of all types of parkinsonism (idiopathic, postencephalitic, and arteriosclerotic) in June 2003 by the FDA. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring, of trihexyphenidyl so providers can direct patient therapy as indicated as part of the interprofessional team.

DYT1 dystonia is an inherited early-onset movement disorder characterized by sustained muscle contractions causing twisting, repetitive movements, and abnormal postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion mutation (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice show motor deficits and reduced striatal dopamine receptor 2 (D2R). Striatal cholinergic interneurons (ChIs) are essential in regulating striatal motor circuits. Multiple dystonia rodent models, including KI mice, show altered ChI firing and modulation. However, due to the errors in assigning KI mice, it is essential to replicate these findings in genetically confirmed KI mice. Here, we found irregular and decreased spontaneous firing frequency in the acute brain slices from Dyt1 KI mice. Quinpirole, a D2R agonist, showed less inhibitory effect on the spontaneous ChI firing in Dyt1 KI mice, suggesting decreased D2R function on the striatal ChIs. On the other hand, a muscarinic receptor agonist, muscarine, inhibited the ChI firing in both wild-type (WT) and Dyt1 KI mice. Trihexyphenidyl, a muscarinic acetylcholine receptor M1 antagonist, had no significant effect on the firing. Moreover, the resting membrane property and functions of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, μ-opioid receptors, and large-conductance calcium-activated potassium (BK) channels were unaffected in Dyt1 KI mice. The results suggest that the irregular and low-frequency firing and decreased D2R function are the main alterations of striatal ChIs in Dyt1 KI mice. These results appear consistent with the reduced dopamine release and high striatal acetylcholine tone in the previous reports.

Woodhouse-Sakati syndrome is a rare, autosomal recessive, multisystemic disorder first identified as a constellation of hypogonadism, mental retardation, diabetes, alopecia, deafness, and electrocardiogram abnormalities. We report a case of a 33-year-old woman who was born to consanguineous parents. She is suffering from hypergonadotropic hypogonadism, extrapyramidal symptoms, hypothyroidism, alopecia, and sensorineural hearing loss. Her MRI showed iron depositions in globus pallidus bilaterally. She underwent genetic testing and was diagnosed with Woodhouse-Sakati syndrome. She was started on trihexyphenidyl to treat her extrapyramidal symptoms. A few months later, she started to have psychotic symptoms in the form of auditory hallucinations and delusions of persecution. Although she exhibited psychotic symptoms after starting trihexyphenidyl, it is less likely to be causing her symptoms since the symptoms started a few months after taking the medication and she was not on high doses. Thus, it is more likely to be a part of Woodhouse-Sakati syndrome.

Dystonia is a movement disorder characterized by involuntary sustained or intermittent muscle contraction causing repetitive twisting movements and abnormal postures. Status dystonicus (SD) is an enigmatic disease of cryptic etiology. We hereby report a child with West syndrome (WS) who went on to develop SD following intramuscular adrenocorticotropic hormone (ACTH) injection. An 11-month-old male child presented with complaints of flexor spasms for 2 months. The diagnosis of WS was confirmed by electroencephalography (EEG), which showed hypsarrhythmia. Intramuscular ACTH was added, and oral trihexyphenidyl was started for dystonia. On day 7 of ACTH, the child developed frequent opisthotonic posturing. Management protocol for grade IV SD was initiated. Administration of N-terminal of ACTH in rat locus coeruleus has been shown to produce human dystonia-like movement and abnormal posturing.

Both human and rodent studies suggest the link between non-rapid eye movement (NREM) sleep and cognition. Recent study indicated that selective activation of cholinergic neurons in basal forebrain inhibits electroencephalogram (EEG) delta power and shortens NREM sleep. In the current study, we aimed to test the pharmacological effect of trihexyphenidyl (THP), a selective muscarinic M1 receptor antagonist, on EEG power spectra and sleep with or without the selective activation of basal forebrain cholinergic neurons. THP (1, 2, and 3 mg/kg) was administrated intraperitoneally in natural sleep phase. Basal forebrain cholinergic neurons expressing modified G protein-coupled muscarinic receptors (hM3Dq) were activated by intraperitoneal injection of clozapine-N-oxide in ChAT-IRES-Cre mice. EEG and electromyogram (EMG) signals were recorded in freely moving mice to analyze EEG power spectrum and sleep hypnogram. Y-maze and novel object recognition tests were used for testing cognition. THP 1 mg/kg significantly increased EEG delta power and facilitated NREM sleep in wildtype mice, while THP 3 mg/kg was required in ChAT-IRES-Cre mice treated with clozapine-N-oxide. THP with dosage up to 8 mg/kg did not induce cognitive impairments in wildtype mice. EEG delta power of NREM sleep is often used as an indicator of sleep depth or sleep quality, which tightly link with sleep-dependent cognition. Taken together, the data collected from rodents hinted that, THP could possibly be used as the NREM sleep facilitator in humans.

Posttraumatic stress disorder (PTSD) can be a chronic and disabling condition. Post-traumatic nightmares (PTNs) form a core component of PTSD and are highly prevalent in this patient population. Nightmares in PTSD have been associated with significant distress, functional impairment, poor health outcomes, and decreased quality of life. Nightmares in PTSD are also an independent risk factor for suicide. Nightmare cessation can lead to improved quality of life, fewer hospital admissions, lower healthcare costs, and reduced all-cause mortality. Effective treatment of nightmares is critical and often leads to improvement of other PTSD symptomatology. However, approved pharmacological agents for the treatment of PTSD have modest effects on sleep and nightmares, and may cause adverse effects. No pharmacological agent has been approved specifically for the treatment of PTNs, but multiple agents have been studied. This current narrative review aimed to critically appraise proven as well as novel pharmacological agents used in the treatment of PTNs. Evidence of varying quality exists for the use of prazosin, doxazosin, clonidine, tricyclic antidepressants, trazodone, mirtazapine, atypical antipsychotics (especially risperidone, olanzapine and quetiapine), gabapentin, topiramate, and cyproheptadine. Evidence does not support the use of venlafaxine, β-blockers, benzodiazepines, or sedative hypnotics. Novel agents such as ramelteon, cannabinoids, ketamine, psychedelic agents, and trihexyphenidyl have shown promising results. Large randomized controlled trials (RCTs) are needed to evaluate the use of these novel agents. Future research directions are identified to optimize the treatment of nightmares in patients with PTSD.

Holmes Tremor (HT) is an irregular, slow-frequency (<4.5 Hz) tremor characterized by a combination of resting, postural, and action tremors mostly of the upper extremities. Symptoms of HT typically emerge 4 weeks to 2 years after a brain injury caused by a spectrum of etiologies. HT pathophysiology is thought to result from aberrant collateral axonal sprouting and synaptic dysfunction following neuronal damage. To date, the dopaminergic nigrostriatal system, cerebello-thalamo-cortical pathway, and dentate-rubro-olivary pathway have all been implicated in the clinical manifestations of HT. The diversity of HT etiologies usually requires a personalized treatment plan. Current treatment options include carbidopa-levodopa, levetiracetam, and trihexyphenidyl, and surgical management such as deep brain stimulation in selected medication-refractory patients. In this review we discuss the pathophysiology, etiology, neuroimaging, and the latest clinical guidelines for care and management of HT.

Introduction Prescription pattern studies conducted in patients with schizophrenia have shown variability in the utilization of antipsychotics based on the geographical location of the study setting. Moreover, there is only a sparse number of studies specifically related to adverse drug reactions (ADRs) in schizophrenia. Hence, a need was felt to study the antipsychotic utilization pattern and adverse drug reactions in patients with schizophrenia in our setting. Methods This was a cross-sectional, observational study conducted at the psychiatry outpatient department (OPD) of a tertiary care hospital in India. Patients diagnosed to have schizophrenia as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) were included in the study provided they had been prescribed antipsychotic medications at the study center for at least three months. The sociodemographic profile of the patients and caregivers was recorded, and prescription pattern assessment was done using WHO core drug use indicators. Information related to ADRs was recorded, and further assessment was done based on the causality, severity, and preventability of ADRs. Results A total of 250 patients were enrolled in the study. Risperidone (40.25%) and olanzapine (26.32%) were the most commonly prescribed antipsychotic drugs, while trihexyphenidyl was the most frequently prescribed concomitant medication. Among the 37 cases of adverse drug reactions that were recorded, amenorrhea, sedation, and weight gain were found to be the most common. The majority of ADRs were of mild severity in addition to being non-preventable. Conclusion It was observed that atypical antipsychotics were commonly prescribed in the study center, and the majority of the ADRs were mild and not preventable, which shows the adequacy of prescribing practices in the current setting.

In this study, we report the first known Turkish case of a novel nonsense mutation c.2453dupT (p.M818fs*28) in the KMT2B (NM_014727.2) gene diagnosed in a male patient with KMT2B-related dystonia (DYT-KMT2B, DYT-28, Dystonia*-28), which is a complex, childhood-onset, progressive, hereditary dystonia. The patient, who is followed up from 9 to 13 years of age, had dysmorphic features, developmental delay, short stature, and microcephaly, in addition to focal dystonia and hemichorea (in the right and left lower extremities). Generalized dystonia involving bulbar and cervical muscles, in addition to dystonic cramps, myoclonus, and hemiballismus, were also observed during the course of the follow-up. While he was able to perform basic functions like eating, climbing stairs, walking, and writing with the aid of levodopa and trihexyphenidyl treatment, his clinical status gradually deteriorated secondary to progressive generalized dystonia in the 4-year follow-up. Deep brain stimulation has been shown to be effective in several patients which could be the next preferred treatment for the patient.

Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is commonly used for the treatment of dystonia associated with TOR1A, otherwise known as DYT1 dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. We previously found that THP normalizes the deficit in striatal dopamine (DA) release in a mouse model of TOR1A dystonia (Tor1a+/ΔE knockin (KI) mice), revealing a plausible mechanism of action for this compound, considering that abnormal DA neurotransmission is consistently associated with many forms of dystonia. However, the mAChR subtype(s) that mediate the rescue of striatal dopamine release remain unclear. In this study we used a combination of pharmacological challenges and cell-type specific mAChR conditional knockout mice of either sex to determine which mAChR subtypes mediate the DA release-enhancing effects of THP. We determined that THP acts in part at M4 mAChR on striatal cholinergic interneurons to enhance DA release in both Tor1a+/+ and Tor1a+/ΔE KI mice. Further, we found that the subtype selective M4 antagonist VU6021625 recapitulates the effects of THP. These data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that subtype selective M4 mAChR antagonists may be effective therapeutics with fewer side effects than THP for the treatment of TOR1A dystonia.

Background: Status dystonicus is a life-threatening, underrecognized movement disorder emergency. We aimed to ascertain the etiology, clinical presentation, complications, and outcomes of status dystonicus in children and reviewed the literature for similar studies. Methods: Records of all children aged <14 years admitted to a single center with status dystonicus between 2014 and 2018 were reviewed. Results: Twenty-four children (75% male) were identified with status dystonicus. The annual incidence rate was 0.05 per 1000 new admissions <12 years of age. The mean age at presentation was 6.3 ± 3.6 years. Median duration of hospital stay was 10.5 days (interquartile range 5-21.7). The severity of dystonia at presentation was grade 3 (n = 9; 37.5%) and 4 (n = 9; 37.5%). The most common triggering factor was intercurrent illness/infection (n = 18; 75%). The most common underlying etiologies were cerebral palsy (n = 8; 33.3%), complicated tubercular meningitis (n = 3; 12.5%), and mitochondrial disorders (n = 3; 12.5%). Basal ganglia involvement was seen in 15 cases (62.5%). Respiratory and/or bulbar compromise (n = 20; 83.3%) and rhabdomyolysis (n = 15; 62.5%) were most commonly seen. Oral trihexyphenidyl (96%) followed by oral or intravenous diazepam (71%), oral baclofen (67%), and midazolam infusion (54%) were the most common drugs used. Clonidine was used in 33% cases, without any significant side effects. Three children died owing to refractory status dystonicus and its complications; the mortality rate was 12.5%. Conclusion Status dystonicus is a neurologic emergency in children with severe dystonia, with significant complications and a high mortality rate. Static and acquired disorders are more common than heredo-familial causes. Identification and treatment of infection in children is important as the majority of cases are triggered by an intercurrent infection.

A drug/proton-antiporter, whose the molecular structure is still unknown, was previously evidenced at the blood-brain barrier (BBB) by functional experiments. The computational method could help in the identification of substrates of this solute carrier (SLC) transporter. Two pharmacophore models for substrates of this transporter using the FLAPpharm approach were developed. The trans-stimulation potency of 40 selected compounds for already known specific substrates ([3H]-clonidine) were determined and compared in the human brain endothelial cell line hCMEC/D3. Results. The two pharmacophore models obtained were used as templates to screen xenobiotic and endogenous compounds from four databases (e.g., Specs), and 45 hypothetical new candidates were tested to determine their substrate capacity. Psychoactive drugs such as antidepressants (e.g., imipramine, desipramine), antipsychotics/neuroleptics such as phenothiazine derivatives (chlorpromazine), sedatives anti-histamine-H1 drugs (promazine, promethazine, triprolidine, pheniramine), opiates/opioids (e.g., hydrocodone), trihexyphenidyl and sibutramine were correctly predicted as proton-antiporter substrates. The best performing pharmacophore model for the proton-antiporter substrates appeared as a good predictor of known substrates and allowed the identification of new substrate compounds. This model marks a new step in the characterization of this drug/proton-antiporter and will be of great use in uncovering its substrates and designing chemical entities with an improved influx capability to cross the BBB.

(1) Background: Over the last decade, misuse and diversion of medications has appeared to be increasingly concerning phenomena, including a range of different molecules. As current knowledge on the abuse of centrally acting anticholinergics is limited, the aim of the present study is to review the relevant published data, focusing on the following molecules: benztropine, biperiden, scopolamine, orphenadrine, and benzhexol/trihexyphenidyl (THP). (2) Methods: A systematic literature review was carried out using Pubmed, Scopus, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Research methods were registered on PROSPERO (CRD42021257293). (3) Results: A total of 48 articles, including case reports, surveys, and retrospective case series analyses, were included. Most articles focused on benzhexol/THP (n = 25), and benztropine (n = 4). The routes of administration were mostly oral, and macrodoses together concomitant illicit drugs, e.g., cocaine, have been recorded. Toxidromes included both physical (e.g., tachycardia, tachypnoea, dilatated pupils, dry skin, urinary retention, ataxia, etc.) and psychiatric symptoms (e.g., anxiety, agitation, delirium, etc.). Fatal outcomes were very rare but reported. (4) Conclusion: Results from the present study show that anticholinergic misusing issues are both widespread worldwide and popular. Considering the potential adverse effects associated, healthcare professionals should be vigilant and monitor eventual misusing issues.

Wilson's disease (WD) or hepatolenticular degeneration is a rare inherited disorder of copper metabolism affecting both the liver and the central nervous system. Psychiatric manifestations may precede neurological signs in the early stages of WD, but catatonia is a rare presentation. Here, we report a case of an 18-year-old girl who presented to the psychiatry outpatient department with catatonia. She was subsequently diagnosed to have WD. Her symptoms improved on treatment with trientine, trihexyphenidyl, zinc acetate, and benzodiazepine.

Parkinson disease is a progressive neurological condition characterized by slowness and paucity of movement (bradykinesia), muscle rigidity, resting tremors, and disordered posture. The onset is typically in the 6th or 7th decade of life with slow progression to akinesia, severe tremors, physical disability and death within 10 to 25 years of initial symptoms. Parkinson disease is common and affects approximately 1% of Americans above the age of 60 years. The cause of Parkinson disease is unknown, but is marked by loss of dopamine-containing neurons in the substantia nigra pars compacta of the brainstem and loss of normal dopaminergic neurotransmission. Therapy of Parkinson disease continues to evolve and has resulted in improved quality of life and survival. The initial agents used for Parkinson disease were anticholinergic agents including trihexyphenidyl (Artane, Trihexy: 1949), benztropine (Cogentin: 1954), and biperiden (Akineton: 1959); their mechanism of action in Parkinsonism is not completely clear. With the increased understanding of the role of dopamine in the pathophysiology of Parkinsonism, agents that directly or indirectly affect dopaminergic transmission have been developed that have resulted in marked improvements in the management of symptoms of Parkinson disease. Levodopa (L-DOPA: 1970) is a metabolic precursor of dopamine and is the single most effective agent for Parkinson disease. It is usually combined with carbidopa (Sinemet: 1975), which increases the drug levels and half life of levodopa by inhibiting the amino acid decarboxylase that metabolizes levodopa peripherally. Dopaminergic receptor agonists are also beneficial in Parkinson disease and are often combined with levodopa/carbidopa. Dopamine receptor agonists currently available include bromocriptine (1978: Parlodel), pergolide (Permax: 1988), apomorphine (Apokyn: 2004) and more selective agonists for the D2 class of dopamine receptors – ropinirole (Requip: 1997), pramipexole (Mirapex: 1997) and rotigotine (Neupro which is formulated in a transdermal patch: 2007). More recently, inhibitors of catechol-O-methyltransferase (COMT) have been developed that block the major enzyme responsible for the metabolism of dopamine; these agents include tolcapone (Tasmar: 1998) and entacapone (Comtan: 2003). Dopamine is also metabolized by the monamine oxidases and selegiline (Atapryl: 2006) and rasagiline (Azilect: 2007) which are specific inhibitors of monamine oxidase (MAO) type B, and are used as an adjunctive therapy with levodopa in therapy of Parkinson disease. Amantadine (Symmetrel: 1987) also has activity in Parkinson disease, perhaps through stimulation of release of dopamine in the substantial nigra. It is discussed separately as an anti-influenza agent. Other agents used in the management of Parkinson disease are used to treat specific complications such as psychosis (pimavanserin: Nuplazid, 2016) and postural hypotension (droxidopa: Vectibix, 2014). Most of the drugs used to treat Parkinson disease have little potential for hepatotoxicity and are rare causes of clinically apparent acute liver injury, the exception being tolcapone. The full references on hepatotoxicity and safety of the drugs for Parkinson disease are given in the discussion of the individual agents listed below.

Holoprosencephaly (HPE) is a central nervous system malformation defined by incomplete separation of the prosencephalon in two hemispheres and determines a broad spectrum of clinical presentations based on extension of non-separation.

No information is available on the use of flavoxate during breastfeeding. Long-term use of trihexyphenidyl might reduce milk production or milk letdown, but a single dose is not likely to interfere with breastfeeding. During long-term use, observe for signs of decreased lactation (e.g., insatiety, poor weight gain).