Emily A. Karanges

Trends in the utilisation of psychotropic medications in Australia from 2000 to 2011.

Objective: This study examined longitudinal trends in the dispensing of psychotropic medications in Australia from January 2000 to December 2011. Method: Dispensing data for the major classes of psychotropic medications (antidepressants, anxiolytics, sedatives, antipsychotics, mood stabilisers and attention-deficit hyperactivity disorder (ADHD) medications) were obtained from the Drug Utilisation Sub-Committee of the Australian Department of Health and Ageing. Results were expressed in terms of defined daily doses/1000 population/day (DDDs/1000/day). Results: There was a 58.2% increase in the dispensing of psychotropic drugs in Australia from 2000 to 2011, driven by major increases in antidepressants (95.3% increase in DDDs/1000/day), atypical antipsychotics (217.7% increase) and ADHD medications (72.9% increase). Dispensing of anxiolytics remained largely unchanged, while sedatives and typical antipsychotics decreased by 26.4% and 61.2%, respectively. Lithium dispensing remained static while valproate and lamotrigine increased markedly. In 2011, antidepressants accounted for 66.9% of total psychotropic DDDs/1000/day totals, far greater than anxiolytics (11.4%), antipsychotics (7.3%), mood stabilisers (5.8%), sedatives (5.5%), or ADHD medications (3.0%). Sertraline, olanzapine, valproate and methylphenidate were the most frequently dispensed antidepressant, antipsychotic, mood stabiliser and ADHD medication, respectively, while diazepam and temazepam were the most commonly dispensed anxiolytic and sedative. Conclusions: Psychotropic utilisation markedly increased in Australia between 2000 and 2011. Some potential concerns include: (1) the continuing high use of benzodiazepines, particularly alprazolam, despite their problematic effects; (2) the rapid increase in serotonin noradrenaline reuptake inhibitor (SNRI) use, given their more complex side-effect profile relative to selective serotonin reuptake inhibitors (SSRIs); and (3) the dramatic increase in antidepressant prescriptions despite questions about the efficacy of these drugs in mild to moderate depression. Finally, some limitations are identified regarding use of the DDDs/1000/day metric, which can distort estimates of utilisation of specific drugs when the defined daily dose is higher or lower than the formulation most commonly dispensed by pharmacies.

Mephedrone in Adolescent Rats: Residual Memory Impairment and Acute but Not Lasting 5-HT Depletion

Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([125I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted.

Longitudinal trends in the dispensing of psychotropic medications in Australia from 2009–2012: Focus on children, adolescents and prescriber specialty

Objective: Longitudinal trends in the dispensing of antidepressant, antipsychotic and ADHD medications from 2009–2012 were examined according to age and gender of patient and prescriber speciality. Of particular interest were changing trends in the prescription of psychotropic medications to children, adolescents and young adults. Method: Dispensing data for government-subsidised antidepressant, antipsychotic and ADHD medications were obtained from the database maintained by the Department of Human Services. Results were expressed in terms of number of prescriptions dispensed. Results: Over the four- year study period, the dispensing of antidepressants, antipsychotics and ADHD medications showed overall increases of 16.1%, 22.7% and 26.1% respectively. The most rapid percentage increases in antidepressant and antipsychotic dispensing occurred in children aged 10–14 (35.5% and 49.1% respectively), while ADHD medication dispensing rose most rapidly in those aged 20–24 (70.9%). Dispensing to males was more common during childhood for all investigated classes while two-thirds of adult antidepressant prescribing was to female patients. The most commonly prescribed antidepressants varied by age and were as follows: fluoxetine (3–19 year olds), desvenlafaxine (20–24 years) and venlafaxine (>25 years). Risperidone was the most common antipsychotic dispensed to children under 15, quetiapine to adolescents and young adults (15–24 years), and olanzapine to adults. Methylphenidate was the most common ADHD medication in those aged under 25, and dexamphetamine the most common in adults. Most antidepressants and antipsychotics were prescribed by GPs (89.9% and 70.6% respectively), while the majority of ADHD medications were prescribed by paediatricians (59.1%). Conclusions: Dispensing of psychotropic medications increased markedly from 2009 to 2012, with notable age-specific trends. General adherence to treatment guidelines is apparent, yet concerns exist regarding rapid increases in serotonin noradrenaline reuptake inhibitor (SNRI) antidepressant prescribing, the likely overmedication of persons with mild psychological distress, and the increasing use of powerful psychotropic medications in younger populations despite uncertain risk–benefit profiles.

Twenty-five years of prescription opioid use in Australia: a whole-of-population analysis using pharmaceutical claims.

AIM The aim of this paper is to investigate 25-year trends in community use of prescribed opioid analgesics in Australia, and to map these trends against major changes to opioid registration and subsidy. METHODS We obtained dispensing data from 1990 to 2014 from two sources: dispensing claims processed under Australias national drug subsidy programme, the Pharmaceutical Benefits Scheme, including under co-payment records from 2012; and estimates of non-subsidized medicine use from a survey of Australian pharmacies (until 2011). Utilization was expressed in defined daily doses (DDD)/1000 population/day. RESULTS Opioid dispensing increased almost four-fold between 1990 and 2014, from 4.6 to 17.4 DDD/1000 pop/day. In 1990, weak, short-acting or orally administered opioids accounted for over 90% of utilization. Use of long-acting opioids increased over 17-fold between 1990 and 2000, due primarily to the subsidy of long-acting morphine and increased use of methadone for pain management. Between 2000 and 2011, oxycodone, fentanyl, buprenorphine, tramadol and hydromorphone use increased markedly. Use of strong opioids, long-acting and transdermal preparations also increased, largely following the subsidy of various opioids for noncancer pain. In 2011, the most dispensed opioids were codeine (41.1% of total opioid use), oxycodone (19.7%) and tramadol (16.1%); long-acting formulations comprised approximately half, and strong opioids 40%, of opioid dispensing. CONCLUSIONS Opioid utilization in Australia is increasing, although these figures remain below levels reported in the US and Canada. The increased use of opioids was largely driven by the subsidy of long-acting formulations and opioids for the treatment of noncancer pain.

Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents?

Selective serotonin reuptake inhibitor use is associated with increased risk of suicidal ideation in adolescent humans, yet the neuropharmacological basis of this phenomenon is unknown. Consequently, we examined the behavioural and neurochemical effects of chronic paroxetine (PRX) treatment in adult and adolescent rats. Rats received PRX in their drinking water (target dose 10 mg/kg) for 22 d, during which time they were assessed for depression- and anxiety-like behaviours. Subsequent ex-vivo analyses examined serum PRX concentrations, striatal neurotransmitter content, and regional serotonin and dopamine transporter (SERT, DAT) binding density. After 11-12 d treatment, PRX-treated adolescent rats showed a significant inhibition of social interaction while adults were unaffected. After 19-20 d treatment, adolescents failed to show an antidepressant-like effect of PRX treatment on the forced swim test (FST), while PRX-treated adults showed a typical decrease in immobility and increase in swimming. Two PRX-treated adolescents died unexpectedly after the FST suggesting a compromised response to physical stress. Despite their greater apparent adverse reaction to the drug, adolescents had significantly lower plasma PRX than adults at day 22 of treatment. Chronic PRX treatment had similar effects in adults and adolescents on striatal 5-HT (unchanged relative to controls) and 5-HIAA levels (decreased), while markers of dopaminergic function (DOPAC, HVA, DA turnover) were increased in adults only. SERT density was up-regulated in the amygdala in PRX-treated adolescents only while DAT density in the nucleus accumbens was down-regulated only in PRX-treated adults. These data suggest that the immature rat brain responds differently to PRX and that this might be of use in modelling the atypical response of human adolescents to antidepressants. The age-specific PRX-induced changes in dopaminergic markers and SERT and DAT binding provide clues as to the neural mechanisms underlying adverse PRX effects in adolescent humans.

Hippocampal protein expression is differentially affected by chronic paroxetine treatment in adolescent and adult rats: a possible mechanism of "paradoxical" antidepressant responses in young persons

Selective serotonin reuptake inhibitors (SSRIs) are commonly recognized as the pharmacological treatment of choice for patients with depressive disorders, yet their use in adolescent populations has come under scrutiny following reports of minimal efficacy and an increased risk of suicidal ideation and behavior in this age group. The biological mechanisms underlying these effects are largely unknown. Accordingly, the current study examined changes in hippocampal protein expression following chronic administration of paroxetine in drinking water (target dose = 10 mg/kg for 22 days) to adult and adolescent rats. Results indicated age-specific changes in protein expression, with paroxetine significantly altering expression of 8 proteins in adolescents only and 10 proteins solely in adults. A further 12 proteins were significantly altered in both adolescents and adults. In adults, protein changes were generally suggestive of a neurotrophic and neuroprotective effect of paroxetine, with significant downregulation of apoptotic proteins Galectin 7 and Cathepsin B, and upregulation of the neurotrophic factor Neurogenin 1 and the antioxidant proteins Aldose reductase and Carbonyl reductase 3. Phosphodiesterase 10A, a signaling protein associated with major depressive disorder, was also downregulated (-6.5-fold) in adult rats. Adolescent rats failed to show the neurotrophic and neuroprotective effects observed in adults, instead displaying upregulation of the proapoptotic protein BH3-interacting domain death agonist (4.3-fold). Adolescent protein expression profiles also suggested impaired phosphoinositide signaling (Protein kinase C: -3.1-fold) and altered neurotransmitter transport and release (Syntaxin 7: 5.7-fold; Dynamin 1: -6.9-fold). The results of the present study provide clues as to possible mechanisms underlying the atypical response of human adolescents to paroxetine treatment.

Psychotropic medication use in Australia, 2007 to 2015: Changes in annual incidence, prevalence and treatment exposure:

Objective: To examine changes in annual patterns of psychotropic medication use in Australia from 2007 to 2015. Methods: We used a 10% sample of individual-level nationwide dispensing claims for concessional beneficiaries dispensed psychotropic medications (stratified by class, subclass) to investigate annual trends and changes in the incidence and prevalence of use, median annual duration of exposure, proportion of people with single psychotropic dispensing and median defined daily doses per person dispensed each medicine per year. Results: Over the study period, there was a 26.1% decrease in the incidence and a 2.6% increase in the prevalence of all psychotropic medicine use. We observed a decrease in the annual incidence and prevalence of antidepressants (11.6% and 16.8%, respectively) but increases in the median annual duration of exposure (7.4%). Amitriptyline had the highest proportion of single dispensings of all antidepressants throughout the study period (26.5% in 2015) and defined daily doses per person dispensed each medicine per year increased by 20% for antidepressants overall. Benzodiazepine use decreased across all measures over the study period apart from long-term use (exposure for >240 days of the year), which in 2015 was 23.6% of those dispensed a benzodiazepine. We observed a relative increase in the incidence and prevalence of antipsychotic use (14.2% and 26.8%, respectively), and haloperidol had the highest proportion of single dispensings of any antipsychotic throughout the study period (47.5% in 2015). We observed a relative increase in the incidence and prevalence of attention-deficit hyperactivity disorder medication use of 114.0% and 101.8%, respectively, over the study period. Conclusion: Increasing doses and treatment durations of antidepressants warrants further investigation due to concerns about overuse. Single dispensings of amitriptyline and haloperidol may indicate off-label use and long-term use of benzodiazepines remains problematic. Despite increases in attention-deficit hyperactivity disorder medication use, prevalence of use is still much lower than the estimated prevalence of attention-deficit hyperactivity disorder in the adult population.

Trends in opioid utilisation in Australia, 2006-2015: insights from multiple metrics

Population‐based observational studies have documented global increases in opioid analgesic use. Many studies have used a single population‐adjusted metric (number of dispensings, defined daily doses [DDDs], or oral morphine equivalents [OMEs]). We combine these volume‐based metrics with a measure of the number of persons dispensed opioids to gain insights into Australian trends in prescribed opioid use.

Contrasting regional Fos expression in adolescent and young adult rats following acute administration of the antidepressant paroxetine

Adolescents and adults may respond differently to antidepressants, with poorer efficacy and greater probability of adverse effects in adolescents. The mechanisms underlying this differential response are largely unknown, but likely relate to an interaction between the neural effects of antidepressants and brain development. We used Fos immunohistochemistry to examine regional differences in adolescent (postnatal day (PND) 28) and young adult (PND 56) male, Wistar rats given a single injection of the selective serotonin reuptake inhibitor paroxetine (10mg/kg). Paroxetine induced widespread Fos expression in both adolescent and young adult rats. Commonly affected areas include the bed nucleus of the stria terminalis (dorsolateral), medial preoptic area, paraventricular hypothalamic and thalamic nuclei and central nucleus of the amygdala. Fos expression was generally lower in adolescents with significantly greater Fos expression observed in young adults in the prelimbic cortex, supraoptic nucleus, basolateral amygdala, lateral parabrachial and Kölliker-Fuse nuclei. However, a small subset of regions showed greater adolescent Fos expression including the nucleus accumbens shell, lateral habenula and dorsal raphe. Paroxetine increased plasma corticosterone concentrations in young adults, but not adolescents. Plasma paroxetine levels were not significantly different between the age groups. These results indicate a different c-Fos signature of acute paroxetine in adolescent rats, with greater activation in key mesolimbic and serotonergic regions, but a more subdued cortical, brainstem and hypothalamic response. This suggests that the atypical response of adolescents to paroxetine may be related to a blunted neuroendocrine response, combined with insufficient top-down regulation of limbic regions involved in reward and impulsivity.

Knowledge and attitudes of Australian general practitioners towards medicinal cannabis: a cross-sectional survey.

Objectives To examine the knowledge and attitudes of Australian general practitioners (GP) towards medicinal cannabis, including patient demand, GP perceptions of therapeutic effects and potential harms, perceived knowledge and willingness to prescribe. Design, setting and participants A cross-sectional survey completed by 640 GPs (response rate=37%) attending multiple-topic educational seminars in five major Australian cities between August and November 2017. Main outcome measures Number of patients enquiring about medicinal cannabis, perceived knowledge of GPs, conditions where GPs perceived it to be beneficial, willingness to prescribe, preferred models of access, perceived adverse effects and safety relative to other prescription drugs. Results The majority of GPs (61.5%) reported one or more patient enquiries about medicinal cannabis in the last three months. Most felt that their own knowledge was inadequate and only 28.8% felt comfortable discussing medicinal cannabis with patients. Over half (56.5%) supported availability on prescription, with the preferred access model involving trained GPs prescribing independently of specialists. Support for use of medicinal cannabis was condition-specific, with strong support for use in cancer pain, palliative care and epilepsy, and much lower support for use in depression and anxiety. Conclusions The majority of GPs are supportive or neutral with regards to medicinal cannabis use. Our results highlight the need for improved training of GPs around medicinal cannabis, and the discrepancy between GP-preferred models of access and the current specialist-led models.