Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease.

BACKGROUND: In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa. METHODS: Levodopa/carbidopa (4:1) was started at age 11 to 13 months, aiming at escalating to 5 to 6 mg/kg levodopa per day. Follow-up focused on dystonia severity and whether self-injury occurred. In addition, the literature was reviewed to delineate the age at onset of self-injury for all reported cases to date. RESULTS: During long-term follow-up, self-injury appears to have been prevented in two patients (now aged 14 and 15.5 years), as their HPRT1 gene mutations had been invariably associated with self-injury before. Future self-injury is unlikely, as only 1.1% of 264 published cases had self-injury onset later in life than these patients' current ages. The third patient started self-injury at age 1.5 years, while on a substantially lower levodopa dose. A clear effect of levodopa on dystonia could not be determined. CONCLUSIONS: Our observations suggest that levodopa, given early enough and sufficiently dosed, might be able to prevent self-injury in LND. Therefore, levodopa could be considered in patients with LND as early as possible, at least before the self-injury appears. Further research is needed to establish very early levodopa as an effective treatment strategy in LND, and to optimize timing and dosing.

Seasonal trends in antidepressant prescribing, depression, anxiety and self-harm in adolescents and young adults: an open cohort study using English primary care data.

BACKGROUND: There is an increasing demand for mental health services for young people, which may vary across the year. OBJECTIVE: To determine whether there are seasonal patterns in primary care antidepressant prescribing and mental health issues in adolescents and young adults. METHODS: This cohort study used anonymised electronic health records from general practices in England contributing to QResearch. It included 5 081 263 males and females aged 14-18 (adolescents), 19-23 and 24-28 years between 2006 and 2019. The incidence rates per 1000 person-years and the incidence rate ratios (IRRs) were calculated for the first records of a selective serotonin reuptake inhibitor (SSRI) prescription, depression, anxiety and self-harm. The IRRs were adjusted for year, region, deprivation, ethnic group and number of working days. FINDINGS: There was an increase in SSRI prescribing, depression and anxiety incidence in male and female adolescents in the autumn months (September-November) that was not seen in older age groups. The IRRs for SSRI prescribing for adolescents peaked in November (females: 1.75, 95% CI 1.67 to 1.83, p<0.001; males: 1.72, 95% CI 1.61 to 1.84, p<0.001, vs in January) and for depression (females: 1.29, 95% CI 1.25 to 1.33, p<0.001; males: 1.29, 95% CI 1.23 to 1.35, p<0.001). Anxiety peaked in November for females aged 14-18 years (1.17, 95% CI 1.13 to 1.22, p<0.001) and in September for males (1.19, 95% CI 1.12 to 1.27, p<0.001). CONCLUSIONS: There were higher rates of antidepressant prescribing and consultations for depression and anxiety at the start of the school year among adolescents. CLINICAL IMPLICATIONS: Support around mental health issues from general practitioners and others should be focused during autumn.

Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD).

BACKGROUND: Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs). OBJECTIVES: To assess the effectiveness and AEs of pharmacological interventions for managing the behaviours of irritability, aggression, and self-injury in ASD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 11 other databases and two trials registers up to June 2022. We also searched reference lists of relevant studies, and contacted study authors, experts and pharmaceutical companies. SELECTION CRITERIA: We included randomised controlled trials of participants of any age with a clinical diagnosis of ASD, that compared any pharmacological intervention to an alternative drug, standard care, placebo, or wait-list control. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were behaviours of concern in ASD, (irritability, aggression and self-injury); and AEs. Secondary outcomes were quality of life, and tolerability and acceptability. Two review authors independently assessed each study for risk of bias, and used GRADE to judge the certainty of the evidence for each outcome. MAIN RESULTS: We included 131 studies involving 7014 participants in this review. We identified 26 studies as awaiting classification and 25 as ongoing. Most studies involved children (53 studies involved only children under 13 years), children and adolescents (37 studies), adolescents only (2 studies) children and adults (16 studies), or adults only (23 studies). All included studies compared a pharmacological intervention to a placebo or to another pharmacological intervention. Atypical antipsychotics versus placebo At short-term follow-up (up to 6 months), atypical antipsychotics probably reduce irritability compared to placebo (standardised mean difference (SMD) -0.90, 95% confidence interval (CI) -1.25 to -0.55, 12 studies, 973 participants; moderate-certainty evidence), which may indicate a large effect. However, there was no clear evidence of a difference in aggression between groups (SMD -0.44, 95% CI -0.89 to 0.01; 1 study, 77 participants; very low-certainty evidence). Atypical antipsychotics may also reduce self-injury (SMD -1.43, 95% CI -2.24 to -0.61; 1 study, 30 participants; low-certainty evidence), possibly indicating a large effect. There may be higher rates of neurological AEs (dizziness, fatigue, sedation, somnolence, and tremor) in the intervention group (low-certainty evidence), but there was no clear evidence of an effect on other neurological AEs. Increased appetite may be higher in the intervention group (low-certainty evidence), but we found no clear evidence of an effect on other metabolic AEs. There was no clear evidence of differences between groups in musculoskeletal or psychological AEs. Neurohormones versus placebo At short-term follow-up, neurohormones may have minimal to no clear effect on irritability when compared to placebo (SMD -0.18, 95% CI -0.37 to -0.00; 8 studies; 466 participants; very low-certainty evidence), although the evidence is very uncertain. No data were reported for aggression or self -injury. Neurohormones may reduce the risk of headaches slightly in the intervention group, although the evidence is very uncertain. There was no clear evidence of an effect of neurohormones on any other neurological AEs, nor on any psychological, metabolic, or musculoskeletal AEs (low- and very low-certainty evidence). Attention-deficit hyperactivity disorder (ADHD)-related medications versus placebo At short-term follow-up, ADHD-related medications may reduce irritability slightly (SMD -0.20, 95% CI -0.40 to -0.01; 10 studies, 400 participants; low-certainty evidence), which may indicate a small effect. However, there was no clear evidence that ADHD-related medications have an effect on self-injury (SMD -0.62, 95% CI -1.63 to 0.39; 1 study, 16 participants; very low-certainty evidence). No data were reported for aggression. Rates of neurological AEs (drowsiness, emotional AEs, fatigue, headache, insomnia, and irritability), metabolic AEs (decreased appetite) and psychological AEs (depression) may be higher in the intervention group, although the evidence is very uncertain (very low-certainty evidence). There was no evidence of a difference between groups for any other metabolic, neurological, or psychological AEs (very low-certainty evidence). No data were reported for musculoskeletal AEs. Antidepressants versus placebo At short-term follow-up, there was no clear evidence that antidepressants have an effect on irritability (SMD -0.06, 95% CI -0.30 to 0.18; 3 studies, 267 participants; low-certainty evidence). No data for aggression or self-injury were reported or could be included in the analysis. Rates of metabolic AEs (decreased energy) may be higher in participants receiving antidepressants (very low-certainty evidence), although no other metabolic AEs showed clear evidence of a difference. Rates of neurological AEs (decreased attention) and psychological AEs (impulsive behaviour and stereotypy) may also be higher in the intervention group (very low-certainty evidence) although the evidence is very uncertain. There was no clear evidence of any difference in the other metabolic, neurological, or psychological AEs (very low-certainty evidence), nor between groups in musculoskeletal AEs (very low-certainty evidence). Risk of bias We rated most of the studies across the four comparisons at unclear overall risk of bias due to having multiple domains rated as unclear, very few rated as low across all domains, and most having at least one domain rated as high risk of bias. AUTHORS' CONCLUSIONS: Evidence suggests that atypical antipsychotics probably reduce irritability, ADHD-related medications may reduce irritability slightly, and neurohormones may have little to no effect on irritability in the short term in people with ASD. There was some evidence that atypical antipsychotics may reduce self-injury in the short term, although the evidence is uncertain. There was no clear evidence that antidepressants had an effect on irritability. There was also little to no difference in aggression between atypical antipsychotics and placebo, or self-injury between ADHD-related medications and placebo. However, there was some evidence that atypical antipsychotics may result in a large reduction in self-injury, although the evidence is uncertain. No data were reported (or could be used) for self-injury or aggression for neurohormones versus placebo. Studies reported a wide range of potential AEs. Atypical antipsychotics and ADHD-related medications in particular were associated with an increased risk of metabolic and neurological AEs, although the evidence is uncertain for atypical antipsychotics and very uncertain for ADHD-related medications. The other drug classes had minimal or no associated AEs.

Multivariable Prediction Modeling of Antidepressant Initiation in Unipolar Depressed Adolescents: A Secondary Analysis of the IMPACT Trial.

Introduction: This secondary analysis of data collected in a randomized controlled trial (RCT) for the treatment of depression in adolescents aimed to test prediction models relating antidepressant (AD) initiation to clinical variables. Methods: The primary study was an RCT where adolescents (ages 11-17) with depression were assigned one of three outpatient psychotherapies over 86 weeks. The current study tested five registered prediction models using data on adolescents not taking ADs at baseline (N = 337). Outcomes of interest included: AD initiation, change in depression severity, and self-injurious thoughts and behaviors (SITBs). Results: Findings from registered analytic strategies were not consistent with our a priori hypotheses; rather we unexpectedly observed a relationship between initiation of AD and increased risk of suicide attempts and suicidal ideation during the same time interval (p > 0.01). Sensitivity analyses found that: (1) higher depressive symptom severity and self-harm each predicted future AD initiation (p < 0.05), and (2) new-onset SITB was associated with AD initiation (p < 0.01). Conclusions: Taken together, our results suggest that depression symptoms severity and SITBs may prompt AD initiation. Researchers may wish to further explore causal pathways relevant to the association ADs between SITBs. Clinicians need to be cognizant of high-quality guideline recommendations when prescribing ADs to adolescents.

Healthcare visits for mental disorders and use of psychotropic medications before and after self-harm in a cohort aged 75.

OBJECTIVES: Non-fatal self-harm (SH) is a major risk factor for late-life suicide. A better knowledge of the clinical management of older adults who self-harm is needed to establish where improvements could be made for the implementation of effective suicide prevention interventions. We therefore assessed contacts with primary and specialised care for mental disorders and psychotropic drug use during the year before and after a late-life non-fatal SH episode. METHOD: Longitudinal population-based study in adults aged ≥75 years with SH episode between 2007 and 2015 retrieved from the regional database VEGA. Healthcare contacts for mental disorders and psychotropic use were assessed during the year before and after the index SH episode. RESULTS: There were 659 older adults who self-harmed. During the year before SH, 33.7% had primary care contacts with a mental disorder, 27.8% had such contacts in specialised care. Use of specialised care increased sharply after the SH, reaching a maximum of 68.9%, but this figure dropped to 19.5% by the end of the year. Use of antidepressants increased from 41% before to 60% after the SH episode. Use of hypnotics was extensive before and after SH (60%). Psychotherapy was rare in both primary and specialised care. CONCLUSION: The use of specialised care for mental disorders and antidepressant prescribing increased after SH. The drop in long-term healthcare visits should be further explored to align primary and specialised healthcare to the needs of older adults who self-harmed. The psychosocial support of older adults with common mental disorders needs to be strengthened.

Association between the pharmacological treatment of bipolar disorder and risk of traumatic injuries: a self-controlled case series study.

BACKGROUND: Patients with bipolar disorder (BPD) are prone to engage in risk-taking behaviours and self-harm, contributing to higher risk of traumatic injuries requiring medical attention at the emergency room (ER).We hypothesize that pharmacological treatment of BPD could reduce the risk of traumatic injuries by alleviating symptoms but evidence remains unclear. This study aimed to examine the association between pharmacological treatment and the risk of ER admissions due to traumatic injuries. METHODS: Individuals with BPD who received mood stabilizers and/or antipsychotics were identified using a population-based electronic healthcare records database in Hong Kong (2001-2019). A self-controlled case series design was applied to control for time-invariant confounders. RESULTS: A total of 5040 out of 14 021 adults with BPD who received pharmacological treatment and had incident ER admissions due to traumatic injuries from 2001 to 2019 were included. An increased risk of traumatic injuries was found 30 days before treatment [incidence rate ratio (IRR) 4.44 (3.71-5.31), p < 0.0001]. After treatment initiation, the risk remained increased with a smaller magnitude, before returning to baseline [IRR 0.97 (0.88-1.06), p = 0.50] during maintenance treatment. The direct comparison of the risk during treatment to that before and after treatment showed a significant decrease. After treatment cessation, the risk was increased [IRR 1.34 (1.09-1.66), p = 0.006]. CONCLUSIONS: This study supports the hypothesis that pharmacological treatment of BPD was associated with a lower risk of ER admissions due to traumatic injuries but an increased risk after treatment cessation. Close monitoring of symptoms relapse is recommended to clinicians and patients if treatment cessation is warranted.

Association between quetiapine use and self-harm outcomes among people with recorded personality disorder in UK primary care: A self-controlled case series analysis.

BACKGROUND: Quetiapine is frequently prescribed to people with personality disorder diagnoses, but this is not supported by evidence or treatment guidelines. AIMS: To examine associations between periods of quetiapine prescribing and self-harm events in people with personality disorder. METHOD: Self-controlled case series using linked primary care and hospital records covering the period 2007-2017. We calculated incidence rates and incidence rate ratios (IRRs) for self-harm events during periods when people were prescribed (exposed to) quetiapine, as well as periods when they were unexposed or pre-exposed to quetiapine. RESULTS: We analysed data from 1,082 individuals with established personality disorder diagnoses, all of whom had at least one period of quetiapine prescribing and at least one self-harm episode. Their baseline rate of self-harm (greater than 12 months before quetiapine treatment) was 0.52 episodes per year. Self-harm rates were elevated compared to the baseline rate in the month after quetiapine treatment was commenced (IRR 1.85; 95% confidence interval (CI) 1.46-2.34) and remained raised throughout the year after quetiapine treatment was started. However, self-harm rates were highest in the month prior to quetiapine initiation (IRR 3.59; 95% CI 2.83-4.55) and were elevated from 4 months before quetiapine initiation, compared to baseline. CONCLUSION: Self-harm rates were elevated throughout the first year of quetiapine prescribing, compared to the baseline rate. However, rates of self-harm reduced in the month after patients commenced quetiapine, compared to the month before quetiapine was initiated. Self-harm rates gradually dropped over a year of quetiapine treatment. Quetiapine may acutely reduce self-harm. Longer-term use and any potential benefits need to be balanced with the risk of adverse events.

Clozapine Reduces Recurrent Suicidal and Self-Injurious Behavior in Treatment-Refractory Incarcerated Individuals.

This retrospective review examines clozapine's effects on treatment-refractory incarcerated individuals (N = 23) with recurrent thoughts of self-harm and/or self-injurious behavior. Emergent suicide risk assessments and days on suicide watch were assessed for the 3 months pre- and post-clozapine treatment. Total suicide assessments fell from 73 pre- to 14 post-clozapine, with a median of 2 assessments (interquartile range [IQR]: 1,5) pre-clozapine compared with 0 (IQR: 0,1) post-clozapine (p < 0.0001). Total days on suicide watch decreased from 104 days pre- to 32 post-clozapine, with a median of 3 days (IQR: 0,9) pre-clozapine compared with 0 (IQR: 0,0) post-clozapine (p = 0.0012). Emergency room visits and medical hospitalizations decreased substantially for all months of treatment. Clozapine treatment was associated with marked reductions in self-injurious thoughts and behaviors in high-risk incarcerated individuals.

N-Acetylcysteine provides limited efficacy as treatment option for skin picking in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed genes in chromosome region 15q11-13. In addition to typical characteristics such as hyperphagia, PWS is evidenced by a certain behavioral phenotype. Common indicators are repetitive behaviors, temper tantrums, and self-injurious behaviors such as skin- and/or rectal picking. N-Acetylcysteine (NAC) was previously described as a promising therapeutic option for skin picking in PWS. In this case series, we retrospectively investigated the effect of pharmacotherapy with NAC in 14 individuals with PWS suffering from skin- and/or rectal picking. Treatment success was determined using the Clinical Global Impression-Improvement scale (CGI-I). The Clinical Global Impression-Efficacy index (CGI-EI) was used to put treatment success and side effects into perspective. Six of fourteen patients, all of which were female, showed improvement in symptoms (dosage 1800-2400 mg/day), whereas six patients did not show any change during treatment. Moreover, two male patients treated for solitary rectal picking showed new onset of skin picking. Across all cases, a CGI-I of 3 (corresponding to minimal improvement) was seen after 3 months of treatment, with a CGI-EI of 1.6 (corresponding to moderate efficacy). NAC remains a reasonable therapeutic option in certain cases of skin picking in PWS but provides only limited efficacy compared to previous studies on the topic. There was a higher rate of adverse drug reactions than previously reported. The results particularly suggest caution in future treatment in individuals with solitary rectal picking and reduced efficacy when coadministered with neuroleptics.

Sertraline as a treatment option for temper outbursts in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by lack of the paternal copy of maternally imprinted, paternally expressed genes at the chromosome 15q11-13 region. In most cases, it is caused by a paternal deletion or a maternal disomy of chromosome 15. Behavioral problems with temper outbursts are common and often combined with physical aggressiveness and self-injury. They are the most frequent cause for a reduced quality of life in adulthood and represent a serious challenge for the individual and those surrounding the individual in everyday life. Until now, no promising pharmaceutical treatment option has been established, and only a few case reports on treatment with selective serotonin reuptake inhibitors (SSRIs) have been reported. In this case series, we investigated the effect of the SSRI sertraline in 14 individuals with PWS frequently showing severe temper outbursts with aggressiveness and self-injuries. After 6 months of treatment with sertraline, 13 of 14 patients (92.6%) either no longer displayed temper outbursts or showed a significant decrease in frequency and severity of temper outbursts. In one case, treatment was stopped due to severe sleep abnormalities. We conclude that sertraline is a promising and safe treatment option for severe temper outbursts in patients with PWS.

Clozapine in the management of persistent destructive behaviour in a 17-year-old boy with intellectual disability.

The management of challenging and refractory destructive behaviour in young patients with intellectual disability (ID) is a major issue faced by families, carers and healthcare professionals who support them. Often, paediatricians and psychiatrists use various behavioural and psychopharmacological approaches, including polypharmacy. We report on one such patient who benefitted greatly from a trial of clozapine, resulting in less aggression, improved quality of life and potentially huge cost savings. We conclude that clozapine may represent a beneficial though seldom-used option for severe, destructive behaviour in young people with ID.

Skin Picking Successfully Treated With Atomoxetine in Comorbid Skin Picking and Attention-Deficit/Hyperactivity Disorder: A Case Report.

"Skin picking disorder" (SPD: also known as neurotic excoriation, psychogenic excoriation, or dermatillomania) is classified in the "obsessive-compulsive and related disorders" category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and characterized by unintentional, repetitive skin picking behaviors. Atomoxetine is a selective noradrenaline reuptake inhibitor used in the treatment of attention-deficit/hyperactivity disorder (ADHD). In this case report, we present a 9-year-old girl with the comorbid diagnosis of ADHD and SPD treated successfully with atomoxetine. To our knowledge, this is the first report of skin picking treated with atomoxetine in a patient with ADHD. We discussed possible explanations of mechanisms. Further studies are required on the effectiveness of atomoxetine for the treatment of SPD in the presence and absence of comorbid ADHD.

Neural correlates of clinical improvement in response to N-acetylcysteine in adolescents with non-suicidal self-injury.

Non-suicidal self-injury (NSSI) is a serious clinical problem that is common in adolescents. Novel, biologically-informed approaches for treating NSSI in adolescents are needed to prevent negative outcomes such as chronic NSSI and future suicide attempts. N-acetylcysteine (NAC) has been used successfully to address other conditions that involve repetitive maladaptive behaviors and may have utility in addressing NSSI. This study explored neural circuit changes following an open-label, 8-week trial of NAC in female adolescents with NSSI. We measured whole-brain resting-state functional connectivity (RSFC) of the amygdala and the nucleus accumbens before and after treatment using resting-state functional neuroimaging. Usable neuroimaging data from both pre- and post-treatment were available for 18 participants. Reduction in NSSI frequency was associated with a decrease in left amygdala RSFC with right supplementary motor area (SMA), but with an increase in right amygdala RSFC with right inferior frontal cortex. For nucleus accumbens, a reduction in NSSI frequency was associated with a decrease in connectivity between right nucleus accumbens and left superior medial frontal cortex. We also report change in similar circuits accompanying clinical improvement in depression and global psychopathology measures. These preliminary findings suggest amygdala and nucleus accumbens-based circuits as potential treatment targets, and set the stage for future research designed to confirm these neural targets using randomized, placebo-controlled designs to confirm clinical efficacy and mechanisms of effect.

Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome: An Initial Cross-Sectional Analysis.

Using a dataset involving 415 individuals with irritability, aggression, agitation and self-injury (IAAS) behaviors from the fragile X syndrome (FXS) FORWARD database, we describe the psychopharmacologic management of IAAS and features of the population of persons with FXS treated with drug therapy for IAAS. Among those with FXS exhibiting IAAS, individuals with FXS receiving drug treatment of IAAS were older, more predominantly male, have more significant intellectual disability, more like to have comorbid autism, hyperarousal, and social impairments. The most commonly utilized medications for IAAS in FXS are antipsychotic medications, specifically aripiprazole and risperidone (37% and 27%, respectively). The majority of subjects (63%) experienced no side effects noted from the use of their psychopharmacologic medications.

Psychopathological disorders in Prader-Willi syndrome. / Alteraciones psicopatológicas en el síndrome de Prader-Willi.

Prader-Willi syndrome is a genetic disorder caused by chromosomal changes in segment 15q11-q13 including cognitive, mental, and behavioral symptoms, as well as a specific physical phenotype. Both the most common psychopathological changes (intellectual disability, obsessions, impulsivity, autism spectrum disorders, self-injuries) and the main psychiatric comorbidities (affective disorders, psychosis, obsessive-compulsive disorder, autism spectrum disorder) are characterized by a great heterogeneity, which warrants the need for better identification of their frequency and clinical signs. In addition to its effects on body compositionand hypotony, growth hormone has been shown to be useful for regulating patient behavior, and psychoactive drugs are also an option. Other alternatives have shown promising results in experimental trials. Adequate understanding of the psychopathology associated to Prader-Willi syndrome would allow for improving clinical approach, symptom identification, detection of comorbidities, and administration of more effective treatments, leading to better clinical outcomes.