Family history of substance use disorder and likelihood of prescription drug misuse in adults 50 and older.

OBJECTIVE: Individuals who are family history positive (FHP) for substance use problems have increased risk for substance use, substance use disorders (SUDs), and psychopathology. Links between FHP status and prescription drug misuse (PDM) have not been well investigated; this study examined PDM in adults 50 and older by FHP status. METHODS: Data were from the US NESARC-III (n = 14,667). Participants reported their opioid PDM, tranquilizer/sedative PDM, SUD, psychopathology, and family history status (i.e. first- and second-degree relatives with alcohol/substance use problems). Prevalence rates were estimated by FHP status, and logistic regressions compared FHP and family history negative (FHN) groups. RESULTS: FHP status was associated with significantly higher rates of PDM (e.g. past-year opioid PDM, FHP: 3.8%, FHN: 1.5%) and SUD from PDM (e.g. past-year SUD, FHP: 1.2%, FHN: 0.2%); also, prevalence varied by family history density, with the highest rates in those with three or more relatives with substance use problems (e.g. past-year opioid PDM: 5.5%). Overall, 32.2% of FHP individuals with past-year PDM had past-year co-occurring SUD and psychopathology diagnoses, versus 11.0% of FHN individuals. CONCLUSION: FHP status could inform treatment decisions in adults 50 and older with conditions for which prescription opioids or tranquilizer/sedatives are indicated.

Prolactin, flupenthixol decanoate and first episode schizophrenia - clinical and laboratory correlates.

First-episode psychosis (FEP) patients are more sensitive to neuroleptic side-effects such as hyperprolactinemia. We examined the prolactin levels of previously minimally treated patients with first episode schizophrenia over their first year of treatment with flupenthixol decanoate and the relationship between prolactin levels, gender and clinical features of schizophrenia. Prolactin levels were assessed at three monthly intervals in 126 patients with first-episode schizophrenia in a single-site study conducted over 12 months during treatment with flupenthixol decanoate according to a fixed protocol. The mean prolactin level for the total sample was 11.91 ng/ml (standard deviation [SD]15.52) at baseline. Women had higher levels of prolactin than men at month 3, 6 and 12, reaching statistical significance at month 12 (p = 0.02). At 12 months more women than men had hyperprolactinemia (defined as more than 20 ng/ml for males, and as more than 25 ng/ml for females (p = 0.007). Using a mixed effect model, there was a significant association between prolactin change scores over 12 months and gender (p = 0.025) as well as Positive and Negative Syndrome Scale (PANSS) total scores (p = 0.001). In addition female gender (p = 0.04) and age (p = 0.02) correlated with the risk of hyperprolactinemia as categorical variable. In this study treatment with flupenthixol decanoate was associated with relatively low levels of hyperprolactinemia, likely owing to flupenthixol's relatively atypical mode of action, as well as to the low doses used in our study. We found an inverse correlation between total PANSS scores and prolactin levels, which could support the suggested theory of prolactin having antipsychotic properties. Our study confirms the importance of gender on the prolactin raising effects of antipsychotic treatment.

Prescription Tranquilizer/Sedative Sources for Misuse in Older Adults.

Background: Older adult prescription tranquilizer/sedative misuse is understudied, despite evidence of increased misuse prevalence and significant associated consequences (e.g., suicidal ideation). Identification of misuse sources could limit such misuse by offering policymakers and clinicians targets to limit diverted tranquilizer/sedative medication. Objective: To establish the prevalence of tranquilizer/sedative misuse sources in older adults and investigate associated poor outcomes. Methods: Data were from the 2009-14 National Survey on Drug Use and Health, including participants endorsing one or more past-month tranquilizer/sedative misuse sources (n = 3,162) with older adult (50-64 and 65 and older; n =160) tranquilizer/sedative source prevalence estimated and compared to younger cohorts. Results: Adults 65 and older had the greatest physician source use (38.2%) across ages. Physician source use in those 50 and older, relative to those obtaining medication from friends/family for free, was linked to a higher prevalence of both past-year prescription opioid misuse (58.6% versus 34.9%) and serious psychological distress (50.1% versus 11.6%). Conclusions/Importance: Physician source use is particularly prevalent in adults 65 and older, and adults 50 and older using physician sources appear at elevated risk of consequences. Careful monitoring of psychiatric symptoms in older adults receiving tranquilizers/sedatives appears warranted. Older adults use a unique pattern of tranquilizer/sedative misuse sources, as compared to younger groups, further signaling that older adult misuse processes differ from those in younger groups.

Relative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning.

BACKGROUND: Bipolar and other psychiatric disorders are associated with considerably increased risk of suicidal behaviour, which may include self-poisoning with medication used to treat the disorder. Therefore, choice of medication for treatment should include consideration of toxicity, especially for patients at risk. The aim of this study was to estimate the relative toxicity of specific drugs within two drug categories, antipsychotics and mood stabilizers, using large-scale databases to provide evidence that could assist clinicians in making decisions about prescribing, especially for patients at risk of suicidal behaviour. METHOD: Two indices were used to assess relative toxicity of mood stabilisers and antipsychotics: case fatality (the ratio between rates of fatal and non-fatal self-poisoning) and fatal toxicity (the ratio between rates of fatal self-poisoning and prescription). Mood stabilisers assessed included lithium [reference], sodium valproate, carbamazepine, and lamotrigine, while antipsychotics included chlorpromazine [reference], clozapine, olanzapine, quetiapine and risperidone. Fatal self-poisoning (suicide) data were provided by the Office for National Statistics (ONS), non-fatal self-poisoning data by the Multicentre Study of Self-harm in England, and information on prescriptions by the Clinical Practice Research Datalink. The primary analysis focussed on deaths due to a single drug. Cases where the drug of interest was listed as the likely primary toxic agent in multiple drug overdoses were also analysed. The study period was 2005-2012. RESULTS: There appeared to be little difference in toxicity between the mood stabilisers, except that based on case fatality where multiple drug poisonings were considered, carbamazepine was over twice as likely to result in death relative to lithium (OR 2.37 95% CI 1.16-4.85). Of the antipsychotics, clozapine was approximately18 times more likely to result in death when taken in overdose than chlorpromazine (single drug case fatality: OR 18.53 95% CI 8.69-39.52). Otherwise, only risperidone differed from chlorpromazine, being less toxic (OR 0.06 95% CI 0.01-0.47). CONCLUSIONS: There was little difference in toxicity of the individual mood stabilisers. Clozapine was far more toxic than the other antipsychotics. The findings are relevant to prescribing policy, especially for patients at particular risk of suicidal behaviour.

Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation).

BACKGROUND: Haloperidol used alone is recommended to help calm situations of aggression or agitation for people with psychosis. It is widely accessible and may be the only antipsychotic medication available in limited-resource areas. OBJECTIVES: To examine whether haloperidol alone is an effective treatment for psychosis-induced aggression or agitation, wherein clinicians are required to intervene to prevent harm to self and others. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (26th May 2016). This register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings, with no language, date, document type, or publication status limitations for inclusion of records into the register. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving people exhibiting aggression and/or agitation thought to be due to psychosis, allocated rapid use of haloperidol alone (by any route), compared with any other treatment. Outcomes of interest included tranquillisation or asleep by 30 minutes, repeated need for rapid tranquillisation within 24 hours, specific behaviours (threat or injury to others/self), adverse effects. We included trials meeting our selection criteria and providing useable data. DATA COLLECTION AND ANALYSIS: We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR), for continuous data we calculated mean difference (MD), and for cognitive outcomes we derived standardised mean difference (SMD) effect sizes, all with 95% confidence intervals (CI) and using a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce 'Summary of findings' tables which included our pre-specified main outcomes of interest. MAIN RESULTS: We found nine new RCTs from the 2016 update search, giving a total of 41 included studies and 24 comparisons. Few studies were undertaken in circumstances that reflect real-world practice, and, with notable exceptions, most were small and carried considerable risk of bias. Due to the large number of comparisons, we can only present a summary of main results.Compared with placebo, more people in the haloperidol group were asleep at two hours (2 RCTs, n=220, RR 0.88, 95%CI 0.82 to 0.95, very low-quality evidence) and experienced dystonia (2 RCTs, n=207, RR 7.49, 95%CI 0.93 to 60.21, very low-quality evidence).Compared with aripiprazole, people in the haloperidol group required fewer injections than those in the aripiprazole group (2 RCTs, n=473, RR 0.78, 95%CI 0.62 to 0.99, low-quality evidence). More people in the haloperidol group experienced dystonia (2 RCTs, n=477, RR 6.63, 95%CI 1.52 to 28.86, very low-quality evidence).Four trials (n=207) compared haloperidol with lorazepam with no significant differences with regard to number of participants asleep at one hour (1 RCT, n=60, RR 1.05, 95%CI 0.76 to 1.44, very low-quality of evidence) or those requiring additional injections (1 RCT, n=66, RR 1.14, 95%CI 0.91 to 1.43, very low-quality of evidence).Haloperidol's adverse effects were not offset by addition of lorazepam (e.g. dystonia 1 RCT, n=67, RR 8.25, 95%CI 0.46 to 147.45, very low-quality of evidence).Addition of promethazine was investigated in two trials (n=376). More people in the haloperidol group were not tranquil or asleep by 20 minutes (1 RCT, n=316, RR 1.60, 95%CI 1.18 to 2.16, moderate-quality evidence). Acute dystonia was too common in the haloperidol alone group for the trial to continue beyond the interim analysis (1 RCT, n=316, RR 19.48, 95%CI 1.14 to 331.92, low-quality evidence). AUTHORS' CONCLUSIONS: Additional data from new studies does not alter previous conclusions of this review. If no other alternative exists, sole use of intramuscular haloperidol could be life-saving. Where additional drugs are available, sole use of haloperidol for extreme emergency could be considered unethical. Addition of the sedating promethazine has support from better-grade evidence from within randomised trials. Use of an alternative antipsychotic drug is only partially supported by fragmented and poor-grade evidence. Adding a benzodiazepine to haloperidol does not have strong evidence of benefit and carries risk of additional harm.After six decades of use for emergency rapid tranquillisation, this is still an area in need of good independent trials relevant to real-world practice.

Rapid Tranquilization for Psychiatric Patients with Psychomotor Agitation: What is Known About it?

Rapid tranquilization is an intervention used in control of agitation or aggression in patients with mental disorders. This study synthesized the available evidence regarding efficacy and safety of drugs used for rapid tranquilization in psychiatric patients with psychomotor agitation. It is an overview study of systematic reviews and meta-analysis of randomized controlled trials (RCT) identified in the database MEDLINE, EMBASE, CINAHL, Web of Science, Cochrane Library and LILACS until April 2015. A team of reviewers, in pairs and independently, identified eligible studies and assessed methodological quality using AMSTAR. Data were extracted from four studies (61 RCT, 8021 participants). The association of haloperidol with promethazine (H + P) promoted tranquilization and presented better safety profile, with moderate quality evidence. Olanzapine demonstrated benefit towards tranquilization and good safety profile, but needed additional administration to keep tranquilization. There was no benefit in the use of haloperidol alone or associated to another psychotropic to most outcomes evaluated. The evidence was of low quality to most of the interventions. H + P was considered a good option for rapid tranquilization, however, more RCT are necessary to confirm the efficacy and safety of the available interventions.

Antipsychotics, mood stabilisers, and risk of violent crime.

BACKGROUND: Antipsychotics and mood stabilisers are prescribed widely to patients with psychiatric disorders worldwide. Despite clear evidence for their efficacy in relapse prevention and symptom relief, their effect on some adverse outcomes, including the perpetration of violent crime, is unclear. We aimed to establish the effect of antipsychotics and mood stabilisers on the rate of violent crime committed by patients with psychiatric disorders in Sweden. METHODS: We used linked Swedish national registers to study 82,647 patients who were prescribed antipsychotics or mood stabilisers, their psychiatric diagnoses, and subsequent criminal convictions in 2006-09. We did within-individual analyses to compare the rate of violent criminality during the time that patients were prescribed these medications versus the rate for the same patients while they were not receiving the drugs to adjust for all confounders that remained constant within each participant during follow-up. The primary outcome was the occurrence of violent crime, according to Sweden's national crime register. FINDINGS: In 2006-09, 40,937 men in Sweden were prescribed antipsychotics or mood stabilisers, of whom 2657 (6·5%) were convicted of a violent crime during the study period. In the same period, 41,710 women were prescribed these drugs, of whom 604 (1·4 %) had convictions for violent crime. Compared with periods when participants were not on medication, violent crime fell by 45% in patients receiving antipsychotics (hazard ratio [HR] 0·55, 95% CI 0·47-0·64) and by 24% in patients prescribed mood stabilisers (0·76, 0·62-0·93). However, we identified potentially important differences by diagnosis-mood stabilisers were associated with a reduced rate of violent crime only in patients with bipolar disorder. The rate of violence reduction for antipsychotics remained between 22% and 29% in sensitivity analyses that used different outcomes (any crime, drug-related crime, less severe crime, and violent arrest), and was stronger in patients who were prescribed higher drug doses than in those prescribed low doses. Notable reductions in violent crime were also recorded for depot medication (HR adjusted for concomitant oral medications 0·60, 95% CI 0·39-0·92). INTERPRETATION: In addition to relapse prevention and psychiatric symptom relief, the benefits of antipsychotics and mood stabilisers might also include reductions in the rates of violent crime. The potential effects of these drugs on violence and crime should be taken into account when treatment options for patients with psychiatric disorders are being considered. FUNDING: The Wellcome Trust, the Swedish Prison and Probation Service, the Swedish Research Council, and the Swedish Research Council for Health, Working Life and Welfare.

Neonatal benzodiazepines exposure during breastfeeding.

OBJECTIVE: To assess central nervous system depression and other adverse effects in infants exposed to benzodiazepines through breast milk. STUDY DESIGN: A prospectively recruited, retrospectively assessed cohort study of mothers who contacted the Motherisk program regarding the safety of benzodiazepines and were invited to participate in a follow-up program regarding the effects of these medications on their infants during lactation. RESULTS: A total of 124 consenting women participated. Adverse outcomes, specifically sedation, was identified in only 1.6% (2 of 124) of infants and was not associated with benzodiazepine dose, number of hours breastfed, or any demographic trait. Mothers reporting adverse outcomes in themselves (26% [32 of 124]) were more likely to be taking concomitantly a greater number of central nervous system depressants. CONCLUSIONS: This study supports the continued recommendation to initiate breastfeeding while taking benzodiazepines postpartum.

Evidence-based pharmacotherapy of panic disorder: an update.

The evidence-based pharmacotherapy of panic disorder continues to evolve. This paper reviews data on first-line pharmacotherapy, evidence for maintenance treatment, and management options for treatment-refractory patients. A Medline search of research on pharmacotherapy was undertaken, and a previous systematic review on the evidence-based pharmacotherapy of panic disorder was updated. Selective serotonin reuptake inhibitors remain a first-line pharmacotherapy of panic disorder, with the serotonin noradrenaline reuptake inhibitor venlafaxine also an acceptable early option. Temporary co-administration of benzodiazepines can be considered. Maintenance treatment reduces relapse rates, but further research to determine optimal duration is needed. For patients not responding to first-line agents several pharmacotherapy options are available, but there is a notable paucity of data on the optimal choice.

A comparison of pharmacoepidemiological study designs in medication use and traffic safety research.

In order to explore how the choice of different study designs could influence the risk estimates, a case-crossover and case-time-control study were carried out and their outcomes were compared with those of a traditional case-control study design that evaluated the association between the exposure to psychotropic medications and the risk of having a motor vehicle accident (MVA). A record-linkage database availing data for 3,786 cases and 18,089 controls during the period 2000-2007 was used. The study designs (i.e., case-crossover and case-time-control) were derived from published literature, and the following psychotropic medicines were examined: antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants, stratified in the two groups selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. Moreover, in order to further investigate the effects of frequency of psychoactive medication exposure on the outcomes of the case-crossover analysis, the data were also stratified by the number of defined daily doses (DDDs) and days of medication use in the 12 months before the motor vehicle accident. Three-thousand seven-hundred fifty-two cases were included in this second part of the case-crossover analysis. The case-crossover design did not show any statistically significant association between psychotropic medication exposure and MVA risk [e.g., SSRIs-Adj. OR = 1.00 (95 % CI: 0.69-1.46); Anxiolytics-Adj. OR = 0.95 (95 % CI: 0.68-1.31)]. The case-time-control design only showed a borderline statistically significant increased traffic accident risk in SSRI users [Adj. OR = 1.16 (95 % CI: 1.01-1.34)]. With respect to the stratifications by the number of DDDs and days of medication use, the analyses showed no increased traffic accident risk associated with the exposure to the selected medication groups [e.g., SSRIs, <20 DDDs-Adj. OR = 0.65 (95 % CI: 0.11-3.87); SSRIs, 16-150 days-Adj. OR = 0.55 (95 % CI: 0.24-1.24)]. In contrast to the above-mentioned results, our recent case-control study found a statistically significant association between traffic accident risk and exposure to anxiolytics [Adj. OR = 1.54 (95 % CI: 1.11-2.15)], and SSRIs [Adj. OR = 2.03 (95 % CI: 1.31-3.14)]. Case-crossover and case-time-control analyses produced different results than those of our recent case-control study (i.e., case-crossover and case-time-control analyses did not show any statistically significant association whereas the case-control analysis showed an increased traffic accident risk in anxiolytic and SSRI users). These divergent results can probably be explained by the differences in the study designs. Given that the case-crossover design is only appropriate for short-term exposures and the case-time-control design is an elaboration of this latter, it can be concluded that, probably, these two approaches are not the most suitable ones to investigate the relation between MVA risk and psychotropic medications, which, on the contrary, are often use chronically.

Prevention of overlapping prescriptions of psychotropic drugs by community pharmacists.

The nonmedical use or abuse of prescription drugs, including psychotropic medicines, is a growing health problem in Japan. Patient access to psychotropic drugs, specifically from the oversupply of medications due to overlapping prescriptions, may increase the risk of drug abuse and dependence. However, very little is known about such overlapping prescriptions. Today, the dispensing of prescriptions is generally moving from inside to outside of hospitals, with psychotropic drugs mainly dispensed at community pharmacies. In this study, we used health insurance claims (i.e., receipts) for dispensing as the main source of information in an investigation of overlapping prescriptions of psychotropic drugs. A total of 119 patients were found to have received overlapping prescriptions, as identified by community pharmacists who were members of the Saitama Pharmaceutical Association, using patient medication records, followed by medication counseling and prescription notes for the patient. According to our findings, the most frequently overlapping medication was etizolam. Etizolam can be prescribed for more than 30 days since it is not regulated under Japanese law as a "psychotropic drug." Generally, when a drug can be prescribed for a greater number of days, it increases the likelihood of an overlapping prescription during the same period. As a result, the long-term prescription of etizolam increases the risk of overlapping prescriptions. We also found that the patients who received overlapping prescriptions of etizolam were mostly elderly and the most common pattern was prescription from both internal medicine and orthopedics physicians. Etizolam has wide range of indications that are covered by health insurance. Our results suggest that patients who received overlapping prescriptions of etizolam may receive prescriptions from different prescribers for different purposes. Therefore, it may be appropriate to regulate etizolam as a "psychotropic drug" under Japanese law, thus setting a limit on the period for which it can be prescribed in order to help prevent long-term and overlapping prescriptions.

Pharmacovigilance in veterinary medicine in Chile: a pilot study.

Iragüen, D., Urcelay, S., San Martín, B. Pharmacovigilance in veterinary medicine in Chile: a pilot study. J. vet. Pharmacol. Therap.34, 108-115. In Chile, there is no present government policy to survey and analyse adverse drug reactions (ADRs) in the field of veterinary medicine. The intent of this study is to assess, for the first time, ADR frequency in treated animals. To this purpose, a 6-month period pilot study based on WHO recommendations was conducted to monitor ADRs in cats and dogs for frequently used drugs and common labelled signs. Of a total of 149 detected ADRs, 29 (6 in cats and 23 in dogs) were notified by means of ADR report forms, while the rest was identified after reviewing patient clinical records, thus evidencing strong under-reporting problems. More than 70% of ADRs were related to antimicrobials, vaccines and tranquilizers. In dogs, there was a significant effect on ADRs' presentation when acepromazine, amoxicillin, carprofen, ivermectin, sextuple vaccine (polyvalent vaccine that confers immunity against canine distemper virus, canine parvovirus, Leptospira canicola, L. icterohemmoragiae, canine adenovirus type 2 and canine parainfluenza virus) and phytomenadione (subcutaneous injection) were administered. In the case of cats, a significant influence on ADRs was detected when acepromazine, amoxicillin or vitamin K was administered. Present results suggest the need for a pharmacovigilance programme in veterinary medicine for timely ADR-presenting drug detection and drug safety improvement.

Sources of prescription opioids and tranquilizers for misuse among U.S. young adults: differences between high school dropouts and graduates and associations with adverse outcomes.

Background and Objectives: Prior research has identified that sources of prescription drugs for misuse vary based on educational attainment, which is important as certain sources are associated with adverse outcomes. The current research addressed limitations of the extant literature by creating distinct categories of push factors for high school dropout (e.g., negative school performance/experiences), pull factors for high school dropout (e.g., starting a family or getting a job), and high school graduates who did not attend college.Methods: Using data from the 2009-2014 National Survey on Drug Use and Health, prevalence of sources were estimated and design-based multivariable logistic regression investigated the association between sources and educational attainment. Additionally, multivariable logistic regression assessed the associations between sources and adverse outcomes (i.e., substance use, substance use disorders, and mental health) separately for each educational category.Results: College respondents were more likely to report "physician" and free from "friend/relative" and less likely to report "purchased" as sources. For most educational categories, "purchasing" prescription drugs was associated with adverse outcomes. Additionally, "theft/fake" prescription emerged as a source associated with adverse outcomes for college respondents, while "friend/relative" was associated with adverse outcomes for high school graduates that did not go on to college.Conclusions: This research has important clinical implications as it identified young adults with a college education as being less likely to obtain prescription drugs from sources known to be associated with adverse outcomes. It also highlighted how associations between sources and adverse outcomes vary based on educational attainment.

Safety and effectiveness of olanzapine and droperidol for chemical restraint for non-consenting adults: a systematic review and meta-analysis.

BACKGROUND: Chemical restraint (CR) is emergency drug management for acute behavioural disturbances in people with mental illness, provided with the aim of rapid calming and de-escalating potentially dangerous situations. AIMS: To describe a systematic review of Randomised Controlled Trials (RCTs) reporting on short-term safety and effectiveness of drugs used for CR, administered to non-consenting adults with mental health conditions, who require emergency management of acute behavioural disturbances. A meta-analysis was conducted of those RCTs with comparable interventions, outcome measures and measurement timeframes. METHOD: Academic databases were searched for RCTs published between 1 January 1996 and 20th April 2020. Relevant RCTs were critically appraised using the 13-item JBI checklist. All RCTs were described, and step-wise filters were applied to identify studies suitable for meta-analysis. For these, forest and funnel plots were constructed, and Q and I2 statistics guided interpretation of pooled findings, tested using MedCalc Version 19.1. RESULTS: Of 23 relevant RCTs, 18 (78.2% total) had excellent methodological quality scores (at least 90%). Eight RCTs were potentially relevant for meta-analysis (six of excellent quality), reporting 20 drug arms in total. Adverse events for 6-36% patients were reported in all 20 drug arms. Four drug arms from two homogenous studies of N = 697 people were meta-analysed. These RCTs tested two antipsychotic drugs (droperidol, olanzapine) delivered intravenously in either 5 mgs or 10 mg doses, with outcomes of time to calm, percentage calm within five or 10 min, and adverse events. There were no significant differences between drug arms for either measure of calm. However, 5 mg olanzapine incurred significantly lower risk of adverse events than 10 mg olanzapine (OR 0.4 (95%CI 0.2-0.8)), although no dose differences were found for droperidol. CONCLUSION: 5 mg intravenous olanzapine is recommended for quick, safe emergency management of people with acute behavioural disturbances associated with mental illness.