Search

Due to the high number of psychotropic drugs with anticholinergic potential, patients taking psychotropic drugs are at high risk for anticholinergic adverse drug reactions (ADRs). The aim of this study was to analyze the prevalence and type of pharmacodynamic anticholinergic drug–drug interactions in psychiatric patients. The retrospective longitudinal analysis used data from a large pharmacovigilance study conducted in ten German psychiatric hospitals. Anticholinergic burden of drugs was defined as “strong” or “moderate” based on current literature. Number and type of anticholinergic drugs were assessed. In total, 27,396 patient cases (45.6% female) with a mean age of 47.3 ± 18.3 years were included. 17.4% (n = 4760) of patients were ≥ 64 years. 35.4% of the patients received between one and four anticholinergic drugs simultaneously. A combination of drugs with anticholinergic potential was detected in 1738 cases (6.3%). Most prescribed drugs were promethazine (n = 2996), olanzapine (n = 2561), biperiden (n = 1074), and doxepin (n = 963). Patients receiving anticholinergic combinations were younger (45.7 vs. 47.4 years, p

To date, only a few studies compared some long-acting injectables (LAIs) antipsychotics showing similar symptom improvement, relapse rates and adherence to treatment. We evaluated the use of LAIs antipsychotics [aripiprazole-1-month (A1M); paliperidone-1-month and 3-month (PP1M and PP3M) and biweekly (2w)-LAIs] and their corresponding oral formulations through (1) the number of hospital re-admissions, (2) the number of documented suicidal behaviour/attempts and (3) the use of concomitant benzodiazepines, oral antipsychotics and biperiden. A total of 277 patients, ≥18 years old, were included if were treated with the corresponding oral or LAI antipsychotic during at least 12 months and were previously diagnosed with schizophrenia. Our results showed that LAIs associated significantly lower suicidal behaviour, reduced the number of hospital admissions, lower diazepam and haloperidol equivalents and mean daily dose of biperiden intake versus oral antipsychotics. Furthermore, significant differences were found between LAIs. Specifically, PP3M was associated to lower hospital admissions versus A1M; PP1M and PP3M lower doses of diazepam equivalents versus 2w-LAIs and finally, PP1M lower antipsychotic intake versus 2w-LAIs. In conclusion, LAIs improved clinical outcomes by reducing the need for concomitant treatments and hospital admissions over oral antipsychotics. PP1M and PP3M showed better outcomes versus A1M and biweekly LAIs.

Clozapine, an antipsychotic developed in 1958, is considered the gold standard and the treatment of choice in treatment-resistant schizophrenia despite its side effects and despite 40-70% of these patients not responding to clozapine. In the last decade, new antipsychotics, such as paliperidone palmitate (PP), have emerged as well as its long acting-injectable (LAI) formulations, available as PP-1-monthly (PP1M) and the newest PP-3-montlhy (PP3M). Despite paliperidone having shown a similar efficacy as others antipsychotics for the treatment of schizophrenia, and that PP3M has been shown to reduce relapses compared to oral formulations, no study has been carried out in treatment-resistant schizophrenia. The aim of our study was to carry out an exploratory evaluation of endocrine and hepatic profiles as well as the concomitant treatments associated to PP3M vs. clozapine, the gold standard, in patients with treatment-resistant schizophrenia. We designed a retrospective study. A total number of 33 patients previously diagnosed as schizophrenics treatment-resistant, who were prescribed clozapine followed by PP1M and PP3M when available, were selected. Demographic data, BMI, hepatic enzymes (glutamic oxaloacetic transaminase, glutamate-pyruvate transaminase and gamma-glutamyl transferase (GGT)], thyroid function (thyroid stimulating hormone), blood platelets and both white and red blood cells as well as the use of concomitant antipsychotics, benzodiazepines and biperiden were compared under treatment with clozapine and PP3M. Antipsychotics and benzodiazepines dosages were compared using by the defined daily dose (DDD) method and haloperidol or diazepam dose equivalents. All statistical analyses were performed using the paired Student t-test for repeated measures. Our data showed that patients under treatment with PP3M showed a significant decrease in BMI (P < 0.01), glucose (P < 0.01), cholesterol (P < 0.05) and triglycerides (P < 0.01) when compared with basal values under treatment with clozapine. Hepatic cholestasis enzyme, GGT, were significantly elevated (P < 0.05) under treatment with clozapine when compared to PP3M. Switching clozapine to PP3M led to a significant lower pharmacological exposure to antipsychotics, by both the DDD (P < 0.05) and haloperidol dose equivalents (P < 0.001) methods without increasing the dose of benzodiazepines while biperiden was more used under PP3M. Finally, antipsychotic monotherapy was higher and less polypharmacy was used with PP3M. In conclusion, our findings suggest that switching clozapine to PP3M improved endocrine and hepatic profile with a lower total exposure to antipsychotics. More studies are needed to truly establish the role of PP3M in treatment-resistant schizophrenia and should be compared against clozapine by using clinical trials.

We present the case of a patient with an atypical course of frontotemporal lobar degeneration (FTLD) complicated by the use of an anticholinergic drug. A 70-year-old patient, followed by psychiatrists for depression and behavioral disorders, received a diagnosis of dementia with Lewy bodies (DLB) at another Center due to auditory hallucinations, gait impairment, and tendency to fall. He was then admitted to our Memory Clinic Unit for behavioral disturbances, such as delusional thinking, auditory hallucinations, and memory complaints. At that time, the patient's therapy included Lorazepam, Quetiapine, Promazine, and Biperiden. The latter was immediately suspended for the absence of extrapyramidal signs and to avoid the anticholinergic cognitive side effects. A 18F-FDG PET showed a derangement of cortical metabolism with diffusely reduced activity, and limited areas of hyperactivity involving lateral frontal and lateral temporal inferior regions bilaterally. The patient underwent a series of exams, including neuropsychological tests, 123I-MIBG scintigraphy, cerebrospinal fluid examination, and genetic analysis. A second 18F-FDG PET showed an extensive remodulation of metabolic activity: relative higher concentration of the tracer in the prefrontal and inferior temporal cortex was no more detectable. Similarly, the diffuse reduced metabolic activity could not be traced anymore. Nonetheless, the metabolic activity still appeared reduced in the frontal lobe, in the anterior cingulate bilaterally, and in the anterior part of the hemispheric fissure. Taken together, clinical and neuroimaging features would point to a FTLD-like form. Furthermore, the diagnostic work-up was likely confounded by the anticholinergic drug on 18F-FDG PET, highlighting the importance of carefully checking the patient's pharmacology during the diagnostic process.

Long-acting injectable antipsychotics (LAIs) have been widely studied in schizophrenia and evidence suggests that they could be also used for the treatment of bipolar and schizoaffective disorders. Nonetheless, there are no studies evaluating their role in other psychiatric disorders. We aimed to evaluate the use of the newest monthly and 3-monthly LAIs—aripiprazole once monthly, paliperidone 1- and 3-monthly (PP1M, PP3M)—against the 2-weekly LAIs, using the following clinical outcomes: (1) the number of hospital re-admissions, (2) the number of documented suicidal behaviors/attempts, and (3) the use of concomitant treatments, including benzodiazepines, oral antipsychotics, and biperiden. A total of 431 patients were included who were treated with the corresponding LAI over at least 12 months and were previously diagnosed with a psychiatric disorder. Statistical analyses were performed using an ANCOVA model, Student’s t test, and the Pearson’s r test. Our results showed significantly decreased re-admissions using PP3M versus the bi-weekly LAIs and aripiprazole once monthly, while no significant differences were found in suicidal behavior. Furthermore, we found a significantly lower intake of benzodiazepines in PP1M and PP3M groups versus the bi-weekly and aripiprazole once-monthly groups. In addition, patients treated with PP1M and PP3M used a significantly lower dose of haloperidol equivalents versus the bi-weekly LAIs group. Finally, significantly higher doses of biperiden were used by the bi-weekly LAIs group. In conclusion, paliperidone LAIs reduced hospital re-admissions and, as aripiprazole once monthly, lowered concomitant psychiatric medication versus the bi-weekly LAIs. Further research and analysis of subgroups are needed; however, these findings might be useful for clinicians.

Background: Increasing evidence has implicated the cholinergic system as a modulator of mood episodes, with possible involvement of nicotinic and/or muscarinic receptors. A number of randomized controlled trials (RCTs) have demonstrated a putative rapid antidepressant effect of the muscarinic antagonist scopolamine. Here, we review the clinical evidence regarding the three principal muscarinic-modulating agents administered in studies involving mood disorders: scopolamine, biperiden and physostigmine. We conduct a meta-analysis on RCTs where these agents were administered to participants experiencing a depressive episode. Methods: A systematic bibliographic search of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies utilizing the above agents was conducted between January 1970 and December 2020. A meta-analysis was subsequently performed on 9 studies which satisfied inclusion criteria, including 322 participants. Results: Administration of scopolamine significantly reduced depressive symptoms compared to placebo, as measured by objective mood rating scales with SMD of -0.95 (95% CI -1.49, -0.42, p = 0.0005). This effect increased to -1.13 (95% CI -1.61, -0.66, p

Biperiden, an antiparkinsonian anticholinergic drug, has been found to inhibit enzymatic hydrolysis of butyrylthiocholine iodide, which is catalyzed by serum cholinesterase. By measuring the difference in the basic and inhibitory hydrolysis reaction rates, in the presence of biperiden as an inhibitor, it is possible to develop a kinetic method for its determination. Both systems, enzyme-substrate-chromogen and enzyme-substrate-chromogen-inhibitor, were characterized by biochemical parameters ( K M = 0.326 – 0.330 mmol dm -3 ; V max = 40 ‑ 99 μmol dm -3 min -1 ), while inhibition was defined as non-competitive with the constant of inhibition K i = 6.142 μmol dm -3 . The reaction conditions have been optimized followed by determination of the calibration curve, the corresponding equation and the limits of detection and quantification yielding 3.84 and 12.80 nmol dm -3 , respectively. Using the calibration chart, it is possible to determine biperiden in different samples in the concentration range of 0.035–35.940 µmol dm -3 . Influence of a number of substances, found in the sample, on the reaction rate was also examined. The optimized method was applied for determination of biperiden in pharmaceutical preparations. Accuracy of the method was tested using the standard addition method. The proposed method has good sensitivity, selectivity, it is simple and fast, and above all easily accessible, and thus applicable in biochemical and pharmaceutical laboratories.

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.

Magnesium oxide (MgO) is a widely used laxative. Because many antipsychotic drugs are lipophilic-basic-compounds, their solubility decreases with increasing pH and changes markedly as the pH of the solution approaches their pKa. It is highly important to clarify the effect of co-administration of MgO on the serum drug concentration for effective, safe, and appropriate medication therapy. However, the relationship between MgO administration and the serum concentration of antipsychotic drugs in patients with schizophrenia has not been reported. Therefore, in the present study, we investigated the effect of MgO administration on the concentration of antipsychotic drugs in the blood of patients with schizophrenia. The serum concentrations of biperiden, zotepine, and risperidone were assayed using an LC/MS system. The correlation between the daily dose of MgO and the relative-drug-concentration (rCp) in each patient was examined. As the MgO dose was increased, the risperidone concentration decreased. The correlation coefficient decreased for risperidone, zotepine, and biperiden, in the same order. To clarify the difference in the suppression potency of MgO on the three drugs, the relationship between the physical properties and the correlation coefficients of each drug was carefully examined. A strong correlation was observed between the pKa and the correlation coefficient. Patients with schizophrenia are often prescribed antipsychotic drugs, which have anticholinergic action and tend to suppress gastric acid secretion. We concluded that basic drug absorption might be suppressed due to an increase in the stomach pH following MgO administration. Therefore, MgO co-administration is better to avoid while taking antipsychotic drugs and anticholinergic drugs.

OBJECTIVES: The present study investigated the effects of biperiden, a muscarinic type 1 antagonist, on the recognition performance of pre-experimentally unfamiliar abstract figures and non-words in healthy young volunteers. The aim was to examine whether 4 mg biperiden could model the recognition memory impairment seen in healthy aging.METHODS: A double-blind, placebo-controlled, two-way crossover study was conducted. We used a three-phase (deep memorization, shallow memorization, and recognition) old/new discrimination paradigm in which memory strength was manipulated. Strong memories were induced by deep encoding and repetition. Deep encoding was encouraged by redrawing the abstract figures and mentioning existing rhyme words for the non-words (semantic processing). Weak memories were created by merely instructing the participants to study the stimuli (shallow memorization).RESULTS: Biperiden impaired recognition accuracy and prolonged reaction times of the drawn and the studied abstract figures. However, participants were biased towards "old" responses in the placebo condition. The recognition of the new abstract figures was unaffected by the drug. Biperiden did not affect the recognition of the non-words.CONCLUSIONS: Although biperiden may model age-related deficits in episodic memory, the current findings indicate that biperiden does not mimic age-related deficits in recognition performance.

Amaç: Biperiden, hem merkezi hem de periferik olarak etki gösteren antikolinerjik bir ajandır. Klinik uygulamada hem nöroleptik tedavinin ekstrapiramidal yan etkilerine hem de Parkinson hastalığının semptomlarına karşı kullanılır. Mevcut çalışmanın amacı farklı dozlarda Biperiden uygulamasının 48 saatlik civciv embriyolarında nöral tüp kapanması üzerindeki potansiyel toksik etkisini belirlemektir. Yöntem: Çalışmada 60 adet döllenmiş yumurta kullanıldı. Tüm yumurtalar kuluçka makinesine yerleştirildi ve her grupta 15 yumurta olacak şekilde dört gruba ayrıldı: Kontrol, BPD1, BPD2 ve BPD3. Yirmi sekiz saatlik inkübasyonda, Biperiden gruplarına subblastodermik olarak üç farklı Biperiden dozu uygulandı. 48 saatlik inkübasyonun sonunda tüm yumurtalar açılarak embriyolar diseke edildi. Embriyolar morfolojik ve histopatolojik olarak değerlendirildi. Bulgular: Mevcut çalışmanın sonuçlarına göre ortalama baş-popo uzunluğu ve somit sayısı dozla orantılı olarak azalma eğilimindeydi. Doz arttıkça deney gruplarında açık nöral tüp ve gelişmemiş embriyo sayısı istatistiksel olarak anlamlı şekilde artmıştır. Somit sayısına göre değerlendirilen embriyoların Hamburger-Hamilton evreleri açısından da gruplar arasında anlamlı fark vardı. Kontrol, BPD1 ve BPD2 gruplarındaki embriyolar evre 13’te, BPD3 grubundakiler ise evre 12’de gözlendi. Sonuç: Çalışmamızda erken civciv embriyolarında Biperiden’in düşük dozda bile nöral tüp kapanmasında teratojeniteye neden olduğunu gösterilmiştir. Doza bağlı olarak somit sayısı ve baş-popo uzunluğu azalmış, yüksek dozda ise gelişim geriliğine neden olmuştur., Objective: Biperiden (BPD) is an anticholinergic agent that acts both centrally and peripherally. It is used to counteract both extrapyramidal side effects of neuroleptic treatment and symptoms of Parkinson’s disease in clinical practice. Current study was layout to determine the potential toxic effect of different doses of Biperiden on neural tube closure in 48hr chick embryos. Method: Sixty fertilized eggs were used in the study. All eggs were placed in the incubator and divided into four groups (15 eggs in each); Control, BPD1, BPD2 and BPD3. At 28hr of incubation, three different doses of Biperiden were administered subblastodermically in all BPD groups. At the end of 48hr of incubation, all eggs were opened and embryos were dissected and evaluated morphologically and histopathologically. Results: According to these results, the mean crown-rump length and somite number tended to decrease proportionally with the dose. As the dose increases, the number of open neural tube and undeveloped embryos in the experimental groups also increases. There was also a significant difference between the groups in terms of Hamburger-Hamilton stages of embryos evaluated according to the number of somite. Embryos in the Control, BPD1 and BPD2 groups were observed at stage 13, and those in the BPD3 group were observed at stage 12. Conclusion: These results showed that Biperiden even in the low dose has teratogenicity on neural tube closure in early chick embryos. The somite numbers and crown-rump length were decreased depending on the dose and Biperiden caused developmental retardation in high doses.

Selective M1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition‐enhancing effects in early‐phase clinical development in healthy subjects is difficult. A challenge with the M1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M1 mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo‐controlled, 3‐way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK‐PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (−2.1 percentage point in adaptive tracking [95%CI, −3.043 to −1.148], verbal memory (2‐3 fewer words recalled [95%CI, −5.9 to −0.2]) and working memory (up to a 50‐millisecond increase in the n‐back task reaction time [95%CI, 21.854‐77.882]) compared with placebo. The PK data were best fitted by a 2‐compartment model and showed high interoccasion and intersubject variability. Population PK‐PD analysis quantified significant concentration‐effect relationships for the n‐back reaction time, n‐back accuracy, and adaptive tracking. In conclusion, biperiden caused M1 mAChR‐related dose‐ and concentration‐dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof‐of‐pharmacology studies and to demonstrate cognition‐enhancing effects of new cholinergic compounds that are being developed.

The aim of the present study was to evaluate the use of oral vs. long-acting injectables (LAIs) antipsychotics, as well as, to compare the effectiveness of different LAI antipsychotics [aripiprazole-1-month, paliperidone-1-month (PP1M), paliperidone-3-month (PP3M) and risperidone long-acting injectable (RLAI)] in patients diagnosed with borderline personality disorder (BPD), by evaluating the following clinical outcomes: (1) the number of hospital admissions; (2) the number of documented suicidal behaviour/attempts; and (3) the use of concomitant treatments, including benzodiazepines, oral antipsychotics and biperiden. We included a total of 116 patients diagnosed with BPD and treated with antipsychotic medication: 50 using a LAI antipsychotic formulation and 66 using the equivalent main oral antipsychotic. Patients treated with LAIs showed a decreased ratio of visits to emergency compared with the oral treatment group, and between LAIs, PP3M vs. aripiprazole-1-month group. Furthermore, patients treated with LAIs used lower number and dose of concomitant antipsychotics compared with patients treated with oral antipsychotics. Moreover, PP1M and PP3M used lower daily dose of diazepam equivalents compared with the aripiprazole-1-month and RLAI treatment groups. In conclusion, the use of LAIs may play a role in the management of BPD.

The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10-20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.

Background Previous studies suggest that muscarinic cholinergic receptors might act upon the dopamine release in the mesolimbic system and alter drug-reinforcing values related to drug craving. Aims We examined the effects of systemic biperiden administration, a muscarinic cholinergic (M1/M4) receptor antagonist, on ethanol (dose of 2 g/Kg) conditioned place preference (CPP), neuronal activation, dopamine and its metabolites levels in the nucleus accumbens. Methods Thirty minutes before the ethanol-induced CPP test, mice received saline or biperiden at doses of 1.0, 5.0, or 10.0 mg/kg. The time spent in each compartment was recorded for 15 min. After the CPP protocol, animals were euthanized, and we investigated the activation of the nucleus accumbens by immunohistochemistry for Fos. We also quantified dopamine, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens by high-performance liquid chromatography (HPLC). Additionally, the rotarod was employed to evaluate the effects of biperiden on motor coordination. Results Biperiden at different doses (1.0, 5.0, and 10.0 mg/kg) blocked the expression of ethanol-induced CPP. These biperiden doses increased the number of Fos-positive cells and the dopamine turnover in the nucleus accumbens. None of the doses affected the motor coordination evaluated by the rotarod. Conclusions Our results show that biperiden can modulate the effect of alcohol reward, and its mechanism of action may involve a change in dopamine and cholinergic mesolimbic neurotransmission.

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. His parents were not consanguineous, and there was no family history of neuropsychiatric diseases. On neurological examination, he showed mild cognitive impairment, saccadic eye pursuit with horizontal gaze nystagmus, mild dysarthria, dystonic posture and movement of the neck, incoordination of both hands, and an ataxic gait. Deep tendon reflexes were normal except for the patellar tendon reflex, which was exaggerated bilaterally. Pathological reflexes were negative and there was no sign of rigidity, sensory disturbance or autonomic dysfunction. Ophthalmological examinations detected thinning of the outer macula lutea in both eyes, indicative of macular dystrophy. After admission, all anti-psychotic drugs were ceased, but his dystonia was unchanged. Levodopa and trihexyphenidyl hydrochloride were not effective. General blood, urine and cerebrospinal fluid examinations showed no abnormalities. Brain MRI showed cerebellar atrophy and bilateral symmetrical thalamic lesions without brainstem atrophy or abnormal signals in the basal ganglia. I123-IMP SPECT also revealed a decreased blood flow in the cerebellum. Genetic screening, including whole exome sequencing conducted by the Initiative on Rare and Undiagnosed Disease identified no possible disease-causing variants. The patient's dystonia worsened and choreic movements manifested on his right hand and foot. We suspected dystonia with marked cerebellar atrophy (DYTCA), but could not exclude drug-induced dystonia. Macular dystrophy and bilateral thalamic lesions on brain MRI have not been previously described in DYTCA. Whether these features might be primarily associated with dystonia or cerebellar ataxia now remains to be determined.

Introduction: Although before, the prioritization of positive and negative symptoms of schizophrenia over neurocognitive impairment was of the highest importance, recent scientific achievements suggest that the disrupted neurocognitive functions are the core clinical feature of schizophrenia. Both general and specific cognitive functions are impaired. Earlier studies promoted atypical antipsychotics as the ones with the pro-cognitive effect, but an increasing number of recent studies do not demonstrate their superiority on neurocognitive improvement over typical antipsychotics. Aim: The aim of this study was to compare the effects of atypical antipsychotics and a combination of typical and atypical antipsychotics on cognitive functions in patients with psychotic disorders. Furthermore, the effects on gender and duration of disorder on the cognitive functioning of patients on different types of antipsychotic therapy were evaluated, as well as the effect of anticholinergic biperiden in patients receiving combined antipsychotic therapy. Subjects and Methods: This academic IV phase quasi-experimental clinical study included 50 hospitalized patients at the Clinic for Psychiatry at the Clinical Center of Vojvodina, who were divided into two groups of 25 subjects-one consisted of patients who had been on treatment with atypical antipsychotics for six weeks at least, while the second group included patients who had been on combined therapy with typical and atypical antipsychotics for minimum of six weeks. Within the second group, two subgroups could have been recognized; one with 12 patients who were co-medicated with anticholinergic biperidine, whilst the rest of 13 patients were using only combined antipsychotic therapy. All patients' cognitive functions were tested using the Mini-Mental State Examination (MMSE) and the results have been analyzed and compared using t-test. Results: There were no statistically significant difference in cognitive functioning between patients using atypical or combined antipsychotic therapy (p>0.05). There is no statistically signifi cant effect on gender or duration of disorder on cognitive functioning in the two compared groups (p>0.05). There is a statistically significant negative effect on cognition due to the co-medication with biperiden during combined antipsychotic therapy (p

The present study was conducted with the objective of further developing the cholinergic hypothesis and not using the prevalent amyloid beta plaque hypothesis or the tau protein hypothesis on dementia. The experiment was conducted on mice using anticholinergic drugs scopolamine and biperiden to investigate the root cause of dementia. First, we measured the mice serum for liquid chromatography-tandem mass spectrometry (LC-MS/MS) after administration of scopolamine and biperiden and found an accumulation of anticholinergic drugs metabolites in the body. The Y-maze test and measurement of LC-MS/MS in the cranial skeletal muscle cells showed that the Scopolamine metabolites have a significant effect on the cranial skeletal muscles, leading to the conclusion that Methocarbamol is an effective treatment for dementia.

Schizophrenia and schizoaffective disorder are chronic and debilitating psychiatric disorders. The present study was designed to determine DNA damage in patients with schizophrenia and schizoaffective disorder to assess the roles of oxidative metabolism and DNA repair mechanisms in this process, to assess the contribution of drugs, and thus to demonstrate the differences between schizophrenia and schizoaffective disorder. Thirty schizophrenia and 30 schizoaffective disorder patients, each having at least five years of disease history, aged between 18 and 60 years with no physical or neurological diseases, and 30 healthy volunteers participated in the study. Psychometric scales were applied, and 5 ml of blood was taken from all participants. The DNA damage was measured in lymphocytes by the comet assay method; the total oxidative parameters by ELISA; OGG1 and NEIL1 gene expressions by real-time PCR; and the role of drugs by in vitro assays. The most important finding in this study was that patients with schizophrenia had significantly greater DNA damage than schizoaffective disorder patients and the controls. This study also provides evidence of high oxidative stress statuses and inadequate DNA repair capacities in patients with schizophrenia. Moreover, psychotropic drugs did not induce any DNA damage to the lymphocytes according to in vitro analyses. The use of clozapine and adequate repair processes of the patients were the decisive factors in the prevention of DNA damage. The results of this study provide a reexamination of schizoaffective disorder within the schizophrenia spectrum and indicate that schizoaffective disorder may be considered a different diagnostic category. © 2018 Elsevier B.V.

Background and Objectives Limited access to medicines can impact negatively on outcomes in people with Parkinson's disease (PD). The study objectives were to determine the availability and assess the affordability of antiparkinsonian medications in pharmacies across Nigeria. Methods This was a cross-sectional nationwide study utilizing the World Health Organization/Health Action Initiative methodology. Strategically selected private- and public-sector pharmacies in the six geopolitical zones of Nigeria were surveyed for availability of medicines for management of early and advanced PD. The nine categories were: levodopa/peripheral decarboxylase inhibitors, dopamine receptor agonists, monoamine oxidase type B inhibitors, anticholinergics, catechol-o-methyl transferase inhibitors, atypical antipsychotics, antidepressants, antidementia drugs, and miscellaneous (e.g., drugs for orthostatism, urinary incontinence, and sleep disturbance). Unaffordability was defined as paying more than 1 days' wages (>N600 or > US$1.67) for a standard 30-day supply. Results One hundred twenty-three pharmacies were surveyed (62 private [50.4%] and 61 public sector [49.6%]; range of 15-25 pharmacies in each geopolitical zone). Private exceeded public-sector availability across all nine categories of PD medicines (P

Introducción. La enfermedad de Parkinson, cuya prevalencia en Colombia es de 4,7 por 1.000 habitantes, constituye un problema de salud pública y un reto terapéutico para los profesionales de la salud.Objetivo. Determinar los patrones de prescripción de fármacos antiparkinsonianos y las variables asociadas con su utilización en una población colombiana.Materiales y métodos. Se hizo un estudio descriptivo de corte transversal. A partir de una base de datos de 3,5 millones de afiliados al sistema de salud, se seleccionaron pacientes con prescripción de medicamentos antiparkinsonianos de manera ininterrumpida entre el 1º de enero y el 31 de marzo de 2015. Se incluyeron variables sociodemográficas, farmacológicas y de medicación concomitante. El análisis multivariado se hizo con el programa IBM SPSS™-22.Resultados. Se hallaron 2.898 pacientes, con una edad media de 65,1 años, de los cuales el 50,7 % correspondía a hombres. El 69,4 % (n=2.010) de las personas recibía monoterapia y el 30,6 %, tratamiento combinado con dos a cinco medicamentos antiparkinsonianos. Los más prescritos eran la levodopa (45,5 %; n=1.318 pacientes), el biperideno (23,1 %; n=670), la amantadina (18,3 %; n=531) y el pramipexol (16,3 %; n=471). La asociación más utilizada fue la de levodopa-carbidopa y entacapone (n=311; 10,7 %). En el análisis multivariado se encontró que ser hombre (odds ratio, OR=1,56; IC95% 1,321-1,837), ser mayor de 60 años (OR=1,41; IC95% 1,112-1,782) y recibir tratamiento en Barranquilla (OR=2,23; IC95% 1,675-2,975), se asociaban con una mayor probabilidad de emplear el tratamiento combinado. Al 68,2 % (n=1.977) de los pacientes se les había prescrito tratamiento concomitante con otros medicamentos.Conclusión. Predominaron los hábitos de prescripción de medicamentos con gran valor terapéutico, principalmente en la monoterapia, la mayoría en las dosis usuales recomendadas. Es necesario explorar la efectividad clínica de las prescripciones estudiadas, y diferenciar entre la enfermedad y los subtipos de síndromes parkinsonianos.

RATIONALE: After stimulation with nitric oxide, soluble guanylate cyclase (sGC) produces cyclic guanosine monophosphate (cGMP), which stimulates an important signalling pathway for long-term potentiation (LTP). By upregulating cGMP, LTP could be stimulated and thereby enhancing memory processes. The present study investigated the effects of the sGC stimulator riociguat on cognition in healthy volunteers. Participants were pre-treated with and without biperiden, which impairs memory performance, to investigate the memory-enhancing effects of riociguat.METHODS: Twenty volunteers participated in a double-blind placebo-controlled six-way crossover design with a cognitive test battery including the verbal learning task (VLT), n-back task, spatial memory test, the attention network test, and a reaction time task. Treatments were placebo and riociguat 0.5 mg, placebo and riociguat 1.0 mg, biperiden 2.0 mg and placebo, biperiden 2.0 mg and riociguat 0.5 mg and biperiden 2.0 mg and riociguat 1.0 mg.RESULTS: Blood pressure was found to be decreased and heart rate to be increased after administration of riociguat. Cognitive performance was not enhanced after administration of riociguat. Biperiden decreased episodic memory on the VLT, yet this deficit was not reversed by riociguat.CONCLUSION: This supports the notion that biperiden might be a valuable pharmacological model to induce episodic memory impairments as observed in AD/MCI.

Experience about the use and safety of anti-Parkinson (anti-PD) medication during pregnancy is scarce. We have retrospectively evaluated the course and outcome of pregnancy in PD patients who used anti-PD medication during their pregnancy. 14 PD patients who used anti-PD medication during part or whole of their pregnancy were included. Dopamine agonists were used in 13 patients, levodopa/benserazide in 4, levodopa/carbidopa/entacapone in 1, rasagiline in 7, amantadine in 4, and biperiden in 1 patient. Nine patients were on combination treatment at the time of their pregnancy. During their whole pregnancy, dopamine agonists had been used in six patients, levodopa in four, and rasagiline in one. Four patients experienced adverse outcomes: one had spontaneous abortion while receiving pramipexole, one elderly mother gave birth to a child with Down syndrome, while receiving pramipexole and rasagiline, in one case, there was fetal distress under levodopa/benserazide, piribedil, and rasagiline which resolved spontaneously, in one case, one of the twins did not survive after the birth while the mother was receiving pramipexole and rasagiline. In none of these cases an association with the use of anti-PD medication and adverse outcomes was clearly established. In one patient, motor symptoms worsened despite high dose levodopa, four others experienced transient worsening upon dose reduction. Results in our case series suggest that levodopa, rasagiline, pramipexole, and ropinirole alone or in combination with each other may be considered relatively safe during pregnancy. Expected benefits and risks should be considered when prescribing anti-PD medication in pregnant women.

Background: In the mental health field, the psychotropic polypharmacy is frequently observed, a significant risk factor for the occurrence of drug interactions. Objective: Identify potential drug interactions on the prescriptions of mental health services users and describe the associated factors. Methods: A cross-sectional study was conducted in 11 services. Sociodemographic data and information about the use of drug were obtained through interviews of users, analysis of prescriptions and medical charts, using a semi-structured questionnaire. Potential drug interactions were identified using the Micromedex® database, the association with sociodemographic characteristics and aspects related to the medicines prescribed were analyzed using the prevalence ratio. Results: The number of medicines prescribed ranged from 0 to 9, with an average of 3.38 (SD=1.76) per user, the most prescribed being haloperidol (12.3%), clonazepam (8.2%) and biperiden (7.9%). The proportion of interactions considering the number of users interviewed was 35.1%. The most frequent between potential interactions were haloperidol and fluoxetine (9.1%); haloperidol and carbamazepine (8.8%); and carbamazepine and chlorpromazine (5.9%). The highest prevalence ratio (PR) for the occurrence of potential interactions was in women (PR=1.36; 95% CI 1.08:1.71), users who had reported improper medicine use (PR=1.36; 95% CI: 1.07:1.72) and those with more than 5 prescribed medicines (PR=1.87; 95% CI: 1.49:2.33). Conclusion: Potential drug interactions were observed in more than one-third of the user’s Brazilian mental health services. The profile of interactions detected could guide the pharmacotherapeutic follow-up of priority users, and help the multidisciplinary team identify signs and symptoms that can influence the treatment of users. Key words: Drug interactions, Drug prescriptions, Psychotropic drugs, Mental health, Mental health services.

Background Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system (CNS). MS with episode of psychosis is a rare entity, and to the best of our knowledge, no case has been reported from Iran till date. Case presentation We report a case of MS with first-episode psychosis in a 27-year-old single man with no history of psychiatric disorder or drug abuse. The patient developed neurological symptoms after 3 months and was finally diagnosed as a case of MS. His symptoms started with behavioral dysfunctions and progressively resulted in depression. Subsequently, treatment was performed with citalopram 20 mg daily, risperidone 2 mg three times a day, and biperiden 2 mg three times a day; however, no improvements in the symptoms were observed. T2-weighted magnetic resonance imaging has demonstrated periventricular and white matter multiple sclerotic plugs with lesions. Eventually, MS was diagnosed after the appearance of paresthesia, upper and lower limb muscle weakness, ataxia, and urinary incontinency as typical signs. Then, the medications were changed to methylprednisolone and interferon therapy, which resulted in improvements in the clinical conditions of the patient. Conclusion Based on the fact that organic disorders such as MS may sometimes appear with initial pure psychiatric symptoms without any neurological signs and symptoms, examinations for symptoms linked to CNS dysfunction, cognitive changes, atypical symptoms, detailed neurological examination, and limited response to conventional antipsychotic drugs are highly recommended to be carried out for patients with first-episode psychosis and even in the followup period.

Introduction Clozapine is an antipsychotic drug that has shown to be more effective than other antipsychotics in the treatment of schizophrenia, but its use is limited due to its side effects, particularly by the risk of causing agranulocytosis. A study was made on the variations in white cell and neutrophil counts in patients treated with Clozapine in a Long-term Psychiatric Unit. Methods A retrospective observational study was conducted with a sample of women of our long-term psychiatric care unit who had been treated with Clozapine. A study was made on the variations in white cell and neutrophil counts during the first 18 weeks of treatment, as well as the onset of leukopenia, neutropenia, agranulocytosis, and the influence of concomitant drugs. Results and conclusions The study included 55 patients on treatment with Clozapine. The incidence rate of neutropenia was 1.82% (95% CI: 0.05–10.13). The incidence rate of leukopenia and agranulocytosis was 0%. An increase in white cell and neutrophil counts from baseline to week 3–4 was observed. Only small variations were observed after this time, but the counts remained higher than the initial values. These changes were statistically significant in the white cell count: One-way repeated ANOVA with Greenhouse–Geisser correction F (11.47, 37) = 2.114 (P = .011); and in neutrophils: One-way repeated ANOVA with Greenhouse–Geisser correction F (10.3, 37) = 3.312 (P = .0002), and MANOVA F (18, 37) = 2.693 (P = .005), η P 2 = 0.567 . The influence of concomitant drugs (lithium, valproic and biperiden) was not significant on the overall increase found in white cells or neutrophils (MANOVA).

Biperiden hydrochloride, (1RS)-1-[(1RS, 2SR, 4RS)-bicyclo[2.2.1]hept-5-en-2-yl]-1-phenyl-3-(piperidin-1-yl)prop an-1-ol hydrochloride, is one of the most efficacious cholinolytics. It is used to treat Parkinson’s disease and various types of muscular spasms and to ameliorate uncoordinated muscular movements that can accompany the use of several tranquilizers [1, 2]. Biperiden appears in the vital and essential drug list that was approved by an order of the RF Government [3].

Neuroleptic malignant syndrome (NMS) is a serious complication associated with the use of drugs that affect dopaminergic system neurotransmission. The occurrence of NMS during pregnancy or gestation is considered a life-threatening obstetric emergency.We are reporting the first case in Latin America of NMS in one pregnant women with acute psychotic episode. One day after starting with antipsychotic therapy, she developed a fever higher than 39.0 °C with tachycardia, tachypnea, generalized muscle rigidity and somnolence, with creatine kinase (CPK) levels evidencing a result of 2800 U/L. She was treated successfully with levetiracetam, biperiden and quetiapine.A search in PubMed, Embase and Ovid from 1988 to 2016 resulted in seven cases reported in either pregnant or puerperal women. In general, NMS resolves within 3-14 days; most NMS cases reported during pregnancy have involved the use of haloperidol (5 case reports) which is concordant with this report. The obstetric results were good in cases reported, only two women showed signs, among them: hyperemesis gravidarum and preterm delivery. Most of the pregnant women who had NMS presented other associated comorbidities, being mostly of infectious origin. In other investigations, it has been affirmed that NMS can become lethal in adults; however, in our search for pregnant women with this disease, no associated mortality was found.NMS is seen infrequently during pregnancy. The clinical diagnosis requires high suspicion by the examiner. It is important that obstetricians timely recognize the condition.

Background: Parkinson’s disease (PD), which occurs in 1% of the population, is the second most common neurodegenerative disorder. Despite the broad spectrum of PD manifestations and high disease prevalence, there are insufficient data on medicine utilization and prescription strategies. The purpose of the current study was to analyze published data concerning treatment approaches and to compare them with Bulgarian therapeutic practice. Design and methods: We conducted a systematic review of the PubMed and Google Scholar databases, and we calculated medicine utilization in Bulgaria during 2018 and 2019 using the WHO methodology. Results: The literature search identified a total of 311 publications, but only 12 met the inclusion criteria. Eleven studies pointed out that levodopa-containing medicine are the most frequently used, followed by dopamine agonists. The highest rate was found for levodopa-containing products and decarboxylase inhibitor (1.06 and 1.33 DDD/1000 inh/day), followed by anticholinergic Biperiden (0.494 and 0.455 DDD/1000 inh/day) during 2018 and 2019 in Bulgaria. Conclusion: Overall, the treatment approaches used in the last decade comply with guideline recommendations, despite variations in levodopa and dopamine agonist utilization. Even though new medicines have been approved for PD management, levodopa- containing products are still most often prescribed and used worldwide. Significance for public health Parkinson’s disease is the second most common neurodegenerative disorder affecting high number of the population. The achieved clinical results and disease control depending on early patients’ diagnostic and treatment. This study emphasizes on medicines utilization and most often used treatment approaches on Parkinson’s disease management. In addition, this is the first study exploring medicines utilization in Bulgaria. The findings reveal real medicines utilization in Bulgaria during 2018-2019 and its comparison with those found in the other countries. Regardless development of new therapies, levodopa-containing products reveals the highest rate of utilization as in most of the compared countries as in Bulgaria

Brain injuries are often associated with the later development of epilepsy. Evidence suggests that morphological and functional changes occur in the remaining neural tissue during a silent (or latent) period in which no seizures are expressed. It is believed that this silent (reorganization) period may provide a therapeutic window for modifying the natural history of disease progression. Here we provide evidence that biperiden, a muscarinic anticholinergic agent, is able to alter disease progression in an animal model of epilepsy. We observed that biperiden was capable of slowing the manifestation of the first spontaneous epileptic seizure and effectively reduced the severity and number of recurrent, spontaneous epileptic seizures during the animals' lifespan. Biomolecular (microdialysis) and electrophysiological (extracellular field recordings) studies determined that biperiden was capable of elevating the threshold of hippocampal excitability, thereby making the hippocampal glutamatergic pathways less responsive to stimuli when high concentrations of potassium were used in vivo or in vitro. Notably, there was no hindrance of long-term memory or learning (a potential problem given the amnestic nature of biperiden). We conclude that biperiden has antiepileptogenic potential and may represent an opportunity for the prevention of post-traumatic epilepsy.

Preclinical and clinical studies suggest that neuronal muscarinic acetylcholine receptor (M-AchR) antagonists have antidepressant-like properties. Despite the recent interest in bicaudal C homolog 1 gene (BICC1) as a target for the treatment of depression, the upstream signaling molecules that regulate BICC1 are unknown, and very few studies have addressed the involvement of BICC1 in the antidepressant-like effects of the selective M1-AchR inhibitor, biperiden. Growing evidence indicates that activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor B (TrkB) signaling may be involved in antidepressant-like activities. In this study, we investigated the role of BDNF/TrkB signaling in the regulation of BICC1 expression in the chronic unpredictable stress (CUS) mouse model of depression. Furthermore, we also examined whether BDNF/TrkB signaling contributes to the antidepressant-like effects of biperiden via down-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. Our current data show that CUS exposure induced significant depression-like behaviors, down-regulation of BDNF/TrkB signaling and up-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. However, biperiden significantly alleviated the CUS-induced abnormalities. Moreover, we found that the effects of biperiden were antagonized by pretreatment with the TrkB antagonist K252a. Our results indicate that BDNF/TrkB signaling may be the major upstream mediator of BICC1 involvement in the antidepressant-like effects of biperiden.

Parkinson's disease (PD) consists of a neurodegenerative pathology that has received a considerable amount of attention because of its clinical manifestations. The most common treatment consists of administering the drugs levodopa and biperiden, which reduce the effectiveness of the disease and the progress of its symptoms. However, phytotherapy treatment of PD has shown great potential in retarding the loss of dopaminergic neurons and minimizing the behavioral abnormalities. The aim of this study is to systematically review the use of supplemental herbal plants with cellular protective effect and behavioral activity in in vivo and in vitro experimental models. A total of 20 studies were summarized, where the effectiveness of herbal extracts and their isolated bioactive compounds was observed in animal models for PD. The main neurochemical mechanisms found in these studies are schematically represented. The herbal extracts and their biocompounds have antioxidant, anti-apoptotic, and antiinflammatory properties, which contribute to avoiding neuronal loss. Reports show that besides acting on the biosynthesis of dopamine and its metabolites, these compounds prevent D2 receptors' hypersensitivity. It is suggested that further studies need be conducted to better understand the mechanisms of action of the bioactive compounds distributed in these plants. Copyright © 2017 John Wiley & Sons, Ltd.

A esquizofrenia e a síndrome de Down são condições prevalentes na população geral, entretanto a comorbidade entre elas é rara. Devido ao escasso material na literatura científica abrangendo tal comorbidade, é justificada a produção científica do presente trabalho. A paciente deste relato de caso tem 15 anos e apresenta síndrome de Down. Foi encaminhada ao Centro de Atenção Psicossocial Infantojuvenil pela Unidade Básica de Saúde em que fazia acompanhamento psiquiátrico. Do ponto de vista psiquiátrico, a paciente apresentava sintomas como solilóquios, alucinações auditivas e delírios, os quais foram melhorando após a introdução e aumento progressivo da olanzapina até a dose de 10 mg/dia. Entretanto, também apresentou ao longo das avaliações sintomas de síndrome extrapiramidal (SEP), controlados com biperideno 4 mg/dia. Além disso, foram constatados sintomas de ansiedade e tricotilomania, manejados com fluoxetina até a dose de 80 mg/dia. Em sua última valiação, a paciente apresentou-se ao serviço com melhora importante dos sintomas psicóticos, porém em alguns momentos com sintomas residuais. Assim como o relato de Buttler et al., nosso caso teve melhora dos sintomas psicóticos com baixa dose do antipsicótico, todavia o relato de Buttler et al. não descreveu a presença de SEP ou sintomatologia residual, o que dificulta a comparação. Em nossa revisão da literatura, não encontramos relatos de esquizofrenia com início precoce em pacientes com síndrome de Down e nenhuma publicação recente sobre o tema. Entretanto, o reconhecimento e o tratamento precoce da comorbidade têm potencial para um melhor prognóstico do quadro.

Objective: Extrapyramidal adverse effects of antipsychotic drugs are more reported in children. Biperiden is an anticholinergic agent to treat the adverse effects of antipsychotic drugs. The drug has the potential to induce delirium at toxic doses. However, data are scarce about delirium associated with biperiden in children. Thus far, a case of delirium has been associated with biperiden in an adolescent patient. We report the first case of delirium associated with the use of biperiden in a preadolescent patient. Case Report: A boy aged five years and weighing 20 kilograms had been diagnosed as having oppositional defiant disorder and separation anxiety disorder in the previous treatment center. Ten milligrams fluoxetine and 0.25 milligrams risperidone had been initiated. On the third day of treatment, dystonia developed and he was administered with biperiden. An hour later, he was brought to our emergency clinic due to disorganized speech and behavior. His vital signs were stable. There were no findings in blood and urine tests. No electrolyte imbalance, liver, kidney, and thyroid dysfunction have been observed. His neurologic examination was unremarkable and no abnormal findings were shown on cranial magnetic resonance imaging. No other system findings or findings pointing out to infectious diseases have been observed. One milligram physostigmine was administered with intravenous infusion. However, symptoms did not resolve and he was diagnosed with delirium. Naranjo Adverse Drug Reaction Probability Scale score was seven, indicating a “Probable” Adverse Drug Reaction. Half milligram haloperidol was administered bid for three days and he was discharged with complete recovery. Conclusion: Clinicians must be aware of the risk of delirium when using non-toxic doses of biperiden in young children.

Biperiden is an anticholinergic agent that acts on the central nervous system. It is used in the treatment of Parkinsonism and extrapyramidal symptoms. Anticholinergic syndrome develops in biperiden poisoning. Physostigmine is an effective central acetylcholinesterase inhibitor. In this article, we aimed to share our experience of using physostigmine in a case of central anticholinergic syndrome developing due to biperidene poisoning in a 4-year-old girl.

Objectives The objective of this study is to report a case of Pisa syndrome due to olanzapine use in an autistic adolescent. Methods The patient was a 12-year-old adolescent girl who was taking olanzapine for autism-related behavioral problems. Abnormal posture and balance problems appeared in the third month of olanzapine treatment. The patient was diagnosed as having Pisa syndrome after clinical evaluation. Biperiden was started on the patient whose complaints continued despite olanzapine treatment was stopped. Patient's complaints regressed with biperiden treatment. Results According to our knowledge, there is no an autistic adolescent case of Pisa syndrome previously reported in the literature. Further studies are needed to clarify the etiology and treatment of Pisa syndrome. Conclusions In patients with balance problems and abnormal posture as a result of olanzapine use, the clinician should keep in mind Pisa syndrome.

Background: Psychotic disorders are characterized by prominent deficits in associative learning and memory for which there are currently no effective treatments. Functional magnetic resonance imaging (fMRI) studies in psychotic disorders have identified deficits in fronto-temporal activation during associative learning and memory. The underlying pathology of these findings remains unclear. Postmortem data have suggested these deficits may be related to loss of muscarinic M-1 receptor mediated signaling. This is supported by an in-vivo study showing improvements in these symptoms after treatment with the experimental M-1/4 receptor agonist xanomeline. The current study tests whether reported deficits in fronto-temporal activation could be mediated by loss of M-1 receptor signaling in psychotic disorders.Methods: Twenty-six medication-free subjects diagnosed with a psychotic disorder and 29 age-, gender-, and IQ-matched healthy controls underwent two functional magnetic resonance imaging (fMRI) sessions, one under placebo and one under selective M-1 antagonist biperiden, while performing the paired associated learning task. M-1 binding potentials (BPND) were measured in the dorsolateral prefrontal cortex (DLPFC) and hippocampus using I-123-IDEX single photon emission computed tomography.Results: In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M-1 antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M-1 receptor binding during learning, with no association found with M-1 receptor binding in the DLPFC. M-1 receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase.Conclusion: The current study is the first to show differences in M-1 receptor mediated functional sensitivity between subjects with a psychotic disorder and controls during a paired associate learning and memory task. Results point to subjects with psychotic disorders having a loss of M-1 receptor reserve in temporal-limbic areas.

Purpose/Background: Biperiden is a muscarinic antagonist that produces memory impairments without impairing attention or motor functions in healthy subjects. It has been suggested that a biperiden-induced memory deficit could model age- and dementia-related memory impairments. The goal of the current study was to determine the dose- and time-dependent effects of biperiden on cognition in healthy volunteers.Methods/Procedures: Twenty-one healthy volunteers participated in a placebo-controlled, 3-way, crossover study. After a baseline test, cognitive performance was tested at 3 time points after a single dose of biperiden 2 or 4 mg, or placebo. Episodic memory was measured using a 15-word verbal learning task (VLT). Furthermore, n-back tasks, a sustained attention to response task and a reaction time task were used, as well as subjective alertness and a side effects questionnaire. In addition, blood serum values and physiological measures were taken.Findings/Results: Biperiden decreased the number of words recalled in immediate and delayed recall of the VLT 90 minutes after drug intake. A dose-dependent impairment was found for the delayed recall, whereas the immediate recall was equally impaired by the 2 doses. Biperiden did not affect the performance on the VLT 4 hours after administration. Performance in the n-back task and the sustained attention to response task were not affected by biperiden at any time point. Both doses were well tolerated as reported side effects were mild at Tmax and were minimal at the other time points.Implications/Conclusions: Biperiden exerts effects on episodic memory without negatively affecting other cognitive performance and behavioral measures that were assessed in this study. The data provide further evidence that biperiden has selective effects on cognition, even after a high dose.

The management of clozapine (CLZ)-induced adverse events affects patient prognoses. Akathisia is a relatively rare adverse event related to CLZ administration and thus the management of this syndrome is not well established. Here, we report a case of treatment-resistant schizophrenia wherein CLZ-induced akathisia was successfully managed with gabapentin enacarbil (GE). The patient was a 39-year-old woman who had been treated with atypical antipsychotics other than CLZ for three years with poor tolerability. Initiation of CLZ (400 mg/day) attenuated her psychotic symptoms, but was followed by moderate akathisia. Neither benzodiazepines nor biperiden improved the akathisia; however, akathisia was finally diminished with co-administration of GE. GE facilitated a dosage increase in CLZ (450 mg/day) for the improved management of pyschotic symptoms, and thus indirectly contributed to treatment of the patient's schizophrenia. We suggest that GE is a useful candidate for the management of CLZ-induced akathisia. The improved management of treatment-induced akathisia and other adverse events can extend the potential application of CLZ for treatment-resistant schizophrenia.

Introdução: Ainda que pouco consensual, a terapêutica antiemética é amplamente utilizada na prática clínica com o objetivo de minimizar a desidratação e diminuir a necessidade de fluidoterapia endovenosa. A escolha do antiemético é de extrema importância, dada a incidência de reações adversas que pode alcançar os 25% em idade pediátrica. Descrição do caso: Adolescente do sexo masculino, com 12 anos de idade, recorreu ao serviço de urgência de um hospital privado por surgimento no próprio dia de cefaleias, um pico febril e um episódio de vómito. Foram administrados paracetamol e metoclopramida endovenosos com melhoria das queixas. Contudo, algum tempo depois, reiniciou um quadro de cefaleias frontais intensas e agitação psicomotora, que motivou a transferência para o serviço de urgência do Serviço Nacional de Saúde. À admissão apresentava-se muito ansioso, queixoso, agitado e desconfortável. No início da observação iniciou um conjunto de movimentos anómalos que dificultavam a comunicação e a realização do exame objetivo, mas sem nunca perder a consciência. Suspeitou-se de uma reação extrapiramidal à administração de metoclopramida endovenosa, tendo sido administrado biperideno endovenoso, com reversão total do quadro clínico. Comentário: Apesar de pouco frequentes, as reações distónicas agudas podem surgir com a dose terapêutica de metoclopramida. Os médicos de medicina geral e familiar contactam com utentes de todas as idades e, como tal, relembra-se a importância de ter sempre presente os possíveis efeitos adversos da medicação, assim como do registo e transmissão da informação relativa às atitudes terapêuticas realizadas, que neste caso foram essenciais. Em idade pediátrica, como alternativa à metoclopramida, a administração de fármacos com segurança bem estabelecida, como o ondansetron e a domperidona, é aconselhada. Introduction: Although not very consensual, antiemetic therapy is widely used in clinical practice in order to minimize dehydration and reduce the need of intravenous fluid therapy. The choice of antiemetic drug is extremely important given the incidence of adverse reactions, which may reach 25% in pediatric age. Case description: A 12-year-old young boy was admitted in the emergency department of a private hospital with complaints of headache, fever and an episode of vomiting. Intravenous paracetamol and metoclopramide were administered, with subsequent improvement of the symptoms. However, sometime later, the patient resumed a severe frontal headache and psychomotor agitation, which led to his transfer to the emergency department of the National Health System. At admission, the patient was very anxious, agitated and uncomfortable. At the beginning of the physical examination, he began to exhibit dystonic movements that made communication difficult and rendered the physical examination impossible to perform, but he never lost consciousness. An extrapyramidal reaction to metoclopramide was suspected and intravenous biperiden was administered, with complete reversal of the clinical presentation. Comment: Although uncommon, acute dystonic reactions may occur within the therapeutic dose of metoclopramide. Family doctors attend patients of all ages; therefore, it is important to keep in mind the possible adverse effects of this medication, as well as to record and transmit information regarding the therapeutic actions performed, which were fundamental in this case. In pediatric age, the administration of others drugs with well-established safety such as ondansetron and domperidone is advised.

Involuntary movements can be a troublesome condition and represent a real challenge for emergency doctors, particularly for patients of paediatric age. We report a case of a 17-year-old boy with painful involuntary movements mostly affecting his mouth and lower limbs, but also the trunk. After reviewing the patient’s history, it was revealed that the adolescent had had acute alcohol intoxication with severe acute agitation and therefore was given a single dose of 10 mg intravenous haloperidol. The concealment of the recent event posed serious difficulties in reaching the diagnosis. When the diagnosis of haloperidol-induced acute dystonia was made, 3 mg of intravenous biperiden was promptly administered with complete clinical resolution in 15 min.

The term epileptogenesis defines the usually durable process of converting normal brain into an epileptic one. The resistance of a significant proportion of patients with epilepsy to the available pharmacotherapy prompted the concept of a causative treatment option consisting in stopping or modifying the progress of epileptogenesis. Most antiepileptic drugs possess only a weak or no antiepileptogenic potential at all, but a few of them appear promising in this regard; these include, for example, eslicarbazepine (a sodium and T-type channel blocker), lamotrigine (a sodium channel blocker and glutamate antagonist) or levetiracetam (a ligand of synaptic vehicle protein SV2A). Among the approved non-antiepileptic drugs, antiepileptogenic potential seems to reside in losartan (a blocker of angiotensin II type 1 receptors), biperiden (an antiparkinsonian drug), nonsteroidal anti-inflammatory drugs, antioxidative drugs and minocycline (a second-generation tetracycline with anti-inflammatory and antioxidant properties). Among other possible antiepileptogenic compounds, antisense nucleotides have been considered, among these an antagomir targeting microRNA-134. The drugs and agents mentioned above have been evaluated in post-status epilepticus models of epileptogenesis, so their preventive efficacy must be verified. Limited clinical data indicate that biperiden in patients with brain injuries is well-tolerated and seems to reduce the incidence of post-traumatic epilepsy. Exceptionally, in this regard, our own original data presented here point to c-Fos as an early seizure duration, but not seizure intensity-related, marker of early epileptogenesis. Further research of reliable markers of early epileptogenesis is definitely needed to improve the process of designing adequate antiepileptogenic therapies.

Acute dystonic reactions are a worrying reason for presentation to the pediatric emergency department and the pediatric neurology clinic in childhood. It must be diagnosed and treated quickly. The aim of this study was to examine the clinical presentations, etiological factors, and prognosis of patients presenting to our regional tertiary pediatric neurology clinic with a diagnosis of acute dystonic reactions in children. Nine pediatric patients who were treated for acute dystonic reactions between May, 2018 and May, 2020 and had adequate follow-up were included in the study. Medical record data were reviewed age, gender, etiology, features of family, treatment, and results. Three of the patients were female and 6 were male. Their average age was 11 years (4–17). All patients were evaluated as a drug-induced acute dystonic reaction. Of the 9 patients, 5 were due to metoclopramide, 3 were due to risperidone, and 1 was due to aripiprazole. It was learned that a similar situation against other drugs developed in the family history of 3 patients. As a treatment, all of them were intramuscularly applied biperiden suitable for their weight and 30 minutes dramatic improvement was observed. Additional dose had to be administered in only 1 case. All cases were discharged for 24 hours. No problem was observed in their follow-up. Drug-induced acute dystonic reaction can be diagnosed and has a clinical picture that completely resolves when effective treatment is applied. However, it should not be forgotten that it can reach life-threatening dimensions clinically.

In this work, the application of matrix-assisted laser desorption ionization (MALDI)-quadrupole time-of-flight (QTOF)-tandem mass spectrometry (MS/MS) to the quantitation of the anticholinergic/antiparkinson drug biperiden in human whole blood, and the estimation of new phase I metabolites of biperiden in human urine, were performed for the first time. The limit of detection of biperiden in human whole blood was 0.3 ng/mL with a quantitation range of 1–100 ng/mL using 20 μL each of whole blood. The developed method was successfully applied to the determination of biperiden in whole blood obtained from two deceased subjects having a history of biperiden treatment. The concentrations of biperiden in the whole blood samples were 1.7 and 17.5 ng/mL. The MALDI-QTOF-MS/MS method was also used to estimate the metabolites of biperiden in urine obtained from the subjects. Six new metabolites formed by hydroxylation and/or dehydration were detected.