Migraine Treatment and Healthcare Resource Utilization in Alberta, Canada.

BACKGROUND: Migraine poses a significant burden worldwide; however, there is limited evidence as to the burden in Canada. This study examined the treatment patterns, healthcare resource use (HRU), and costs among newly diagnosed or recurrent patients with migraine in Alberta, Canada, from the time of diagnosis or recurrence. METHODS: This retrospective observational study utilized administrative health data from Alberta, Canada. Patients were included in the Total Migraine Cohort if they had: (1) ≥1 International Classification of Diseases diagnostic code for migraine; or (2) ≥1 prescription dispense(s) for triptans from April 1, 2012, to March 31, 2018, with no previous diagnosis or dispensation code from April 1, 2010, to April 1, 2012. RESULTS: The mean age of the cohort (n = 199,931) was 40.0 years and 72.3% were women. The most common comorbidity was depression (19.7%). In each medication class examined, less than one-third of the cohort was prescribed triptans and fewer than one-fifth was prescribed a preventive. Among patients with ≥1 dispense, the mean rate of opioid prescriptions was 4.61 per patient-year, compared to 2.28 triptan prescriptions per patient-year. Migraine-related HRU accounted for 3%-10% of all use. CONCLUSION: Comorbidities and high all-cause HRU were observed among newly diagnosed or recurrent patients with migraine. There is an underutilization of acute and preventive medications in the management of migraine. The high rate of opioid use reinforces the suboptimal management of migraine in Alberta. Migraine management may improve by educating healthcare professionals to optimize treatment strategies.

Burden of Episodic Migraine, Chronic Migraine, and Medication Overuse Headache in Alberta.

OBJECTIVE: To describe demographic and clinical characteristics, healthcare resource use, costs, and treatment patterns in three migraine cohorts. METHODS: This retrospective observational study using administrative data examined patients with episodic migraine (EM), chronic migraine (CM) (without medication overuse headache [MOH]), and medication overuse headache in Alberta, Canada. Migraine patients were identified between 2012 and 2018 based on ≥ 1 diagnostic codes or triptan prescription. Patients with CM were defined using parameter estimates of a logistic regression model, and MOH was defined as patients with an average of ≥ 15 supply days covered of acute medications. EM was defined as patients without CM or MOH. Study outcomes were summarized using descriptive statistics. RESULTS: Patients with EM (n = 144,574), CM (n = 27,283), and MOH (n = 11,485) were included. Higher rates of healthcare use and costs were observed for CM (mean [SD] all-cause cost: ($12,693 [40,664]) and MOH ($16,611.5 [$38,748]) versus episodic migraine ($4,251 [$40,637]). Across all cohorts, opioids were the most dispensed acute medication (range across cohorts: 31.7%-89.8%), while antidepressants and anticonvulsants were the most dispensed preventive medication. Preventative medication classes were used by a minority of patients in each cohort, except anticonvulsants, where 50% of medication overuse patients had a dispensation. CONCLUSIONS: Patients with CM and MOH have a greater burden of illness compared to patients with EM. The overutilization of acute medication, particularly opioids, and the underutilization of preventive medications highlight an unmet need to more effectively manage migraine.

Epidemiology and treatment utilization for Canadian patients with migraine: a literature review.

The objective of this narrative review was to identify real-world evidence regarding the burden of migraine in Canada. We conducted a literature search in MEDLINE, Embase, and the Cochrane Database of Systematic Reviews for studies published between August 2010 and August 2020. Of the 3269 publications identified, 29 studies were included. Prevalence estimates varied widely across Canada, and mental health comorbidities were common. Individuals with migraine have a lower quality of life, detrimental impact on workforce productivity, and higher rates of health care resource utilization (HCRU), with HCRU and costs highest among those with chronic migraine. We found inconsistencies in care, including underutilization of medications such as triptans, and varied utilization of over-the-counter and prescription medications. Increased medication use was identified among those with chronic migraine, and only a small number of patients used migraine preventive medications. The burden of migraine in Canada is substantial. Reduced quality of life and workforce productivity, increased HCRU and costs, and underutilization of triptans and migraine preventive medications highlight an important need for more effective management of individuals with migraine.

Anxiety symptoms in working patients with major depressive disorder treated with vortioxetine: associations with clinical and treatment outcomes in the AtWoRC study.

BACKGROUND: Anxiety symptoms are common in patients with major depressive disorder (MDD) and usually confer worse treatment outcomes. The long-term, open-label AtWoRC study in working patients with MDD treated with vortioxetine demonstrated a significant correlation between severity of anxiety symptoms and impaired work productivity. This analysis was undertaken to further explore clinical characteristics and treatment outcomes in patients with different levels of severity of anxiety symptoms at baseline. METHODS: Post hoc analysis in 199 working patients with MDD treated with vortioxetine (10-20 mg/day), stratified by Generalized Anxiety Disorder 7-item (GAD-7) score at baseline [mild/moderate anxiety (GAD-7 ⩽14), n = 83; severe anxiety (GAD-7 ⩾15), n = 116]. Associations were examined between GAD-7 and other outcome assessment scores at baseline. Observed mean changes from baseline to week 52 were compared between groups. RESULTS: Patients with severe anxiety had significantly worse depressive and cognitive symptoms, functioning, and work productivity at baseline than those with mild/moderate anxiety, but similar cognitive performance. Statistically significant improvements from baseline were seen for all outcomes after 52 weeks of vortioxetine treatment, with no significant differences observed between the two groups after adjustment for baseline anxiety scores. CONCLUSION: Treatment with vortioxetine was associated with long-term improvement in clinical symptoms and measures of work productivity in patients with MDD in a real-world setting, irrespective of severity of anxiety symptoms at the start of treatment.

Improvements in Workplace Productivity in Working Patients With Major Depressive Disorder: Results From the AtWoRC Study.

OBJECTIVE: To assess changes in workplace productivity and functioning in an open-label study in working patients receiving vortioxetine (10 to 20 mg/d) for major depressive disorder (MDD). METHODS: Associations between items in the Work Limitations Questionnaire (WLQ), the Sheehan Disability Scale (SDS), and the Work Productivity and Activity Impairment (WPAI) questionnaire were assessed at 12 and 52 weeks by Pearson correlation coefficients. RESULTS: Significant improvements were observed across all domains of workplace productivity and functioning after 12 and 52 weeks' vortioxetine treatment. Strong correlations were seen between improvements in WLQ mental domains and WPAI presenteeism and SDS work/school items. Presenteeism showed stronger correlations with other workplace productivity measures than absenteeism. CONCLUSIONS: Presenteeism and absenteeism impact productivity in working patients with MDD. Vortioxetine confers long-term benefits across all workplace functioning domains.

Canadian economic impact of improved workplace productivity in patients with major depressive disorder treated with vortioxetine.

OBJECTIVE: The AtWoRC study is an interventional, open-label Canadian study that demonstrated significant improvements in cognitive function and workplace productivity in patients with major depressive disorder (MDD) treated with vortioxetine for a current major depressive episode. The objective of the present analysis was to assess the Canadian economic impact of improved workplace productivity based on the AtWoRC study results. METHODS: The economic impact of improved productivity in patients with MDD treated with vortioxetine was assessed over a 52-week period considering productivity loss due to absenteeism and presenteeism using the standard human capital approach and an employer's perspective. Absenteeism was measured with the Work Productivity and Activity Impairment questionnaire; and presenteeism with the Work Limitation Questionnaire. Productivity gains following treatment initiation with vortioxetine were estimated using the difference from baseline. RESULTS: In the AtWoRC study, patients at baseline reportedly missed, in the past 7 days, an average of 8.1 h due to absenteeism and 3.0 h due to presenteeism. Following 52 weeks of treatment with vortioxetine, patients reportedly missed an average of 4.9 h due to absenteeism and 2.0 h due to presenteeism. This improved workplace productivity translated into savings of C$110.64 for 1 week of work following 52 weeks of treatment. The cumulative 52-week economic impact showed potential savings of C$4,550 when factoring in the cost of therapy. CONCLUSION: This study suggested that workplace productivity gain due to an improvement in symptoms of MDD following treatment with vortioxetine will lead to substantial cost savings for the Canadian economy.

Real-life assessment of aripiprazole monthly (Abilify Maintena) in schizophrenia: a Canadian naturalistic non-interventional prospective cohort study.

BACKGROUND: With previously established efficacy of aripiprazole once-monthly injectable formulation (AOM) in pre-registration randomized controlled trials, the current study was designed to evaluate its effectiveness in patients treated for schizophrenia in regular clinical settings in Canada. METHODS: Following their clinicians' decision to prescribe AOM, 193 patients with a diagnosis of schizophrenia, were recruited from 17 Canadian community or hospital-based settings. The primary outcome of global functioning was assessed with the Global Assessment of Functioning Scale (GAF) at 3-month intervals for 1 year. Secondary outcomes (social and occupational functioning and illness severity) and adverse drug reactions (ADR) were also assessed. RESULTS: A majority of the 169 evaluable patients were within the first 5 years of diagnosis (early phase). A linear mixed model analysis showed a significant main effect of time (Type III test p < 0.001) after adjusting for baseline GAF score, with a change in mean GAF scores from 49 at baseline to 61 at 12 months. No differences between early vs late phase were observed. Results on secondary outcome measures of function (Social and Occupational Functioning Scale) and illness severity (Clinical Global Impression-Severity Scale and Brief Psychiatric Rating Scale) were similar. Serious ADRs were observed in 29 (14.6%) patients and akathisia in 18 (9.1%) patients. At month-12, significant (≥7%) weight gain was observed in 25.7% (n = 27/105) of patients. CONCLUSIONS: Treatment with AOM is effective in improving symptoms and functioning in schizophrenia patients treated in regular clinical settings. Akathisia was infrequent while one quarter of patients gained clinically significant weight. TRIAL REGISTRATION: Unique identifier: NCT02131415 . First posted: 06 May 2014.

Long-term functioning outcomes are predicted by cognitive symptoms in working patients with major depressive disorder treated with vortioxetine: results from the AtWoRC study.

OBJECTIVE: AtWoRC (Assessment in Work productivity and the Relationship with Cognitive symptoms) was an interventional, open-label, Canadian study (NCT02332954) designed to assess the association between cognitive symptoms and workplace productivity in working patients with major depressive disorder (MDD) receiving vortioxetine. METHODS: Eligible patients with MDD received vortioxetine (10-20 mg/day) and were assessed over 52 weeks at visits emulating a real-life setting (n = 199). Partial correlation between changes in patient-reported cognitive symptoms (20-item Perceived Deficits Questionnaire-Depression; PDQ-D-20) and workplace productivity (Work Limitations Questionnaire; WLQ) was assessed at 12 and 52 weeks. Additional assessments included depression severity, cognitive performance, and patient-reported functioning. Structural equations model (SEM) analyses assessed causal relationships between changes in measures of cognition and functioning over time, adjusted for improvements in depressive symptoms. RESULTS: Statistically significant improvements in all outcomes from baseline to week 52 were seen in the overall population and both subgroups (first treatment and switch). Response and remission rates were 77% and 56%, respectively. Improvements in PDQ-D-20 and WLQ productivity loss scores at weeks 12 and 52 were significantly correlated. SEM analyses found patient-rated cognitive symptoms (PDQ-D-20) at weeks 12 and 26 were significantly predictive (p < 0.05) of patient-reported functioning (Sheehan Disability Scale) at the subsequent visit. Depression severity and objectively measured cognitive performance did not significantly predict functional outcomes at any timepoint. CONCLUSION: These results demonstrate the long-term benefits of vortioxetine treatment in working patients with MDD and emphasize the strong association between cognitive symptoms and functioning in a real-world setting.

Assessment in Work Productivity and the Relationship with Cognitive Symptoms (AtWoRC): primary analysis from a Canadian open-label study of vortioxetine in patients with major depressive disorder (MDD).

OBJECTIVE: The Assessment in Work Productivity and the Relationship with Cognitive Symptoms (AtWoRC) study aimed to assess the association between cognitive symptoms and work productivity in gainfully employed patients receiving vortioxetine for a major depressive episode (MDE). METHODS: Patients diagnosed with major depressive disorder (MDD) and treated with vortioxetine independently of study enrollment were assessed over 52 weeks at visits that emulated a real-life setting. Patients were classified as those receiving vortioxetine as the first treatment for their current MDE (first treatment) or having shown inadequate response to a previous antidepressant (switch). The primary endpoint was the correlation between changes in patient-reported cognitive symptoms (20-item Perceived Deficits Questionnaire [PDQ-D-20]) and changes in work productivity loss (Work Limitations Questionnaire [WLQ]) at week 12. Additional assessments included changes in symptom and disease severity, cognitive performance, functioning, work loss, and safety. RESULTS: In the week 12 primary analysis, 196 eligible patients at 26 Canadian sites were enrolled, received at least one treatment dose, and attended at least one postbaseline study visit. This analysis demonstrated a significant, strong correlation between PDQ-D-20 and WLQ productivity loss scores (r=0.634; p<0.001), and this correlation was significant in both first treatment and switch patients (p<0.001). A weaker correlation between Digit Symbol Substitution Test and WLQ scores was found (r=-0.244; p=0.003). CONCLUSION: At 12 weeks, improvements in cognitive dysfunction were significantly associated with improvements in workplace productivity in patients with MDD, suggesting a role for vortioxetine in functional recovery in MDD.

Serotonin-induced cleavage of the atypical protein kinase C Apl III in Aplysia.

A constitutively active kinase, known as protein kinase Mζ (PKMζ), is proposed to act as a long-lasting molecular memory trace. While PKMζ is formed in rodents through translation of a transcript initiating in an intron of the protein kinase Cζ (PKCζ) gene, this transcript does not exist in Aplysia californica despite the fact that inhibitors of PKMζ erase memory in Aplysia in a fashion similar to rodents. We have previously shown that, in Aplysia, the ortholog of PKCζ, PKC Apl III, is cleaved by calpain to form a PKM after overexpression of PKC Apl III. We now show that kinase activity is required for this cleavage. We further use a FRET reporter to measure cleavage of PKC Apl III into PKM Apl III in live neurons using a stimulus that induces plasticity. Our results show that a 10 min application of serotonin induces cleavage of PKC Apl III in motor neuron processes in a calpain- and protein synthesis-dependent manner, but does not induce cleavage of PKC Apl III in sensory neuron processes. Furthermore, a dominant-negative PKM Apl III expressed in the motor neuron blocked the late phase of intermediate-term facilitation in sensory-motor neuron cocultures induced by 10 min of serotonin. In summary, we provide evidence that PKC Apl III is cleaved into PKM Apl III during memory formation, that the requirements for cleavage are the same as the requirements for the plasticity, and that PKM in the motor neuron is required for intermediate-term facilitation.

Aplysia cell adhesion molecule and a novel protein kinase C activity in the postsynaptic neuron are required for presynaptic growth and initial formation of specific synapses.

To explore the role of both Aplysia cell adhesion molecule (ApCAM) and activity of specific protein kinase C (PKC) isoforms in the initial formation of sensory neuron synapses with specific postsynaptic targets (L7 but not L11), we examined presynaptic growth, initial synapse formation, and the expression of the presynaptic neuropeptide sensorin following cell-specific reduction of ApCAM or of a novel PKC activity. Synapse formation between sensory neurons and L7 begins by 3 h after plating and is accompanied by a rapid accumulation of a novel PKC to sites of synaptic interaction. Reducing ApCAM expression specifically from the surface of L7 blocks presynaptic growth and initial synapse formation, target-induced increase of sensorin in sensory neuron cell bodies and the rapid accumulation of the novel PKC to sites of interaction. Selective blockade of the novel PKC activity in L7, but not in sensory neurons, with injection of a dominant negative construct that interferes with the novel PKC activity, produces the same actions as downregulating ApCAM; blockade of presynaptic growth and initial synapse formation, and the target-induced increase of sensorin in sensory neuron cell bodies. The results indicate that signals initiated by postsynaptic cell adhesion molecule ApCAM coupled with the activation of a novel PKC in the appropriate postsynaptic neuron produce the retrograde signals required for presynaptic growth associated with initial synapse formation, and the target-induced expression of a presynaptic neuropeptide critical for synapse maturation.

Role of protein kinase C in the induction and maintenance of serotonin-dependent enhancement of the glutamate response in isolated siphon motor neurons of Aplysia californica.

Serotonin (5-HT) mediates learning-related facilitation of sensorimotor synapses in Aplysia californica. Under some circumstances 5-HT-dependent facilitation requires the activity of protein kinase C (PKC). One critical site of PKC's contribution to 5-HT-dependent synaptic facilitation is the presynaptic sensory neuron. Here, we provide evidence that postsynaptic PKC also contributes to synaptic facilitation. We investigated the contribution of PKC to enhancement of the glutamate-evoked potential (Glu-EP) in isolated siphon motor neurons in cell culture. A 10 min application of either 5-HT or phorbol ester, which activates PKC, produced persistent (> 50 min) enhancement of the Glu-EP. Chelerythrine and bisindolylmaleimide-1 (Bis), two inhibitors of PKC, both blocked the induction of 5-HT-dependent enhancement. An inhibitor of calpain, a calcium-dependent protease, also blocked 5-HT's effect. Interestingly, whereas chelerythrine blocked maintenance of the enhancement, Bis did not. Because Bis has greater selectivity for conventional and novel isoforms of PKC than for atypical isoforms, this result implicates an atypical isoform in the maintenance of 5-HT's effect. Although induction of enhancement of the Glu-EP requires protein synthesis (Villareal et al., 2007), we found that maintenance of the enhancement does not. Maintenance of 5-HT-dependent enhancement appears to be mediated by a PKM-type fragment generated by calpain-dependent proteolysis of atypical PKC. Together, our results suggest that 5-HT treatment triggers two phases of PKC activity within the motor neuron, an early phase that may involve conventional, novel or atypical isoforms of PKC, and a later phase that selectively involves an atypical isoform.

The atypical protein kinase C in Aplysia can form a protein kinase M by cleavage.

In vertebrates, a brain-specific transcript from the atypical protein kinase C (PKC) zeta gene encodes protein kinase M (PKM) zeta, a constitutively active kinase implicated in the maintenance of synaptic plasticity and memory. We have cloned the atypical PKC from Aplysia, PKC Apl III. We did not find a transcript in Aplysia encoding PKMzeta, and evolutionary analysis of atypical PKCs suggests formation of this transcript is restricted to vertebrates. Instead, over-expression of PKC Apl III in Aplysia sensory neurons leads to production of a PKM fragment of PKC Apl III. This cleavage was induced by calcium and blocked by calpain inhibitors. Moreover, nervous system enriched spliced forms of PKC Apl III show enhanced cleavage. PKC Apl III could also be activated through phosphorylation downstream of phosphoinositide 3-kinase. We suggest that PKM forms of atypical PKCs play a conserved role in memory formation, but the mechanism of formation of these kinases has changed over evolution.