Tubers Affecting the Fusiform Face Area Are Associated with Autism Diagnosis.

OBJECTIVE: Tuberous sclerosis complex (TSC) is associated with focal brain "tubers" and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms. METHODS: We delineated tuber locations for 115 TSC participants with ASD (n = 31) and without ASD (n = 84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network. We tested for associations between ASD diagnosis and tuber burden within the whole brain, specific lobes, and at 8 regions of interest derived from the ASD neuroimaging literature, including the anterior cingulate, orbitofrontal and posterior parietal cortices, inferior frontal and fusiform gyri, superior temporal sulcus, amygdala, and supplemental motor area. Next, we performed an unbiased data-driven voxelwise lesion symptom mapping (VLSM) analysis. Finally, we calculated the risk of ASD associated with positive findings from the above analyses. RESULTS: There were no significant ASD-related differences in tuber burden across the whole brain, within specific lobes, or within a priori regions derived from the ASD literature. However, using VLSM analysis, we found that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD. INTERPRETATION: Although TSC is a rare cause of ASD, there is a strong association between tuber involvement of the right FFA and ASD diagnosis. This highlights a potentially causative mechanism for developing autism in TSC that may guide research into ASD symptoms more generally. ANN NEUROL 2023;93:577-590.

Tuber Locations Associated with Infantile Spasms Map to a Common Brain Network.

OBJECTIVE: Approximately 50% of patients with tuberous sclerosis complex develop infantile spasms, a sudden onset epilepsy syndrome associated with poor neurological outcomes. An increased burden of tubers confers an elevated risk of infantile spasms, but it remains unknown whether some tuber locations confer higher risk than others. Here, we test whether tuber location and connectivity are associated with infantile spasms. METHODS: We segmented tubers from 123 children with (n = 74) and without (n = 49) infantile spasms from a prospective observational cohort. We used voxelwise lesion symptom mapping to test for an association between spasms and tuber location. We then used lesion network mapping to test for an association between spasms and connectivity with tuber locations. Finally, we tested the discriminability of identified associations with logistic regression and cross-validation as well as statistical mediation. RESULTS: Tuber locations associated with infantile spasms were heterogenous, and no single location was significantly associated with spasms. However, >95% of tuber locations associated with spasms were functionally connected to the globi pallidi and cerebellar vermis. These connections were specific compared to tubers in patients without spasms. Logistic regression found that globus pallidus connectivity was a stronger predictor of spasms (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.10-3.50, p = 0.02) than tuber burden (OR = 1.65, 95% CI = 0.90-3.04, p = 0.11), with a mean receiver operating characteristic area under the curve of 0.73 (±0.1) during repeated cross-validation. INTERPRETATION: Connectivity between tuber locations and the bilateral globi pallidi is associated with infantile spasms. Our findings lend insight into spasm pathophysiology and may identify patients at risk. ANN NEUROL 2021;89:726-739.

Making new choices about antidepressants in Australia: the long view 1975-2002.

OBJECTIVE: To examine trends in types of antidepressant medications prescribed in Australia between 1975 and 2002. DESIGN: Sales data from the Australian pharmaceutical industry were used to examine trends in overall antidepressant prescribing and changes in the types of antidepressants prescribed between 1975 and 2002. MAIN OUTCOME MEASURES: Antidepressant sales were expressed as defined daily doses (DDDs) per 1000 people per day, using the estimated Australian population for each year obtained from the Australian Bureau of Statistics. RESULTS: Average annual growth in the sales of antidepressants was 1.1% per year from 1975 to 1990, after which growth rose steeply to reach 29% in 1995. By 2002 the rate of growth had slowed to 6.6%. Eighty per cent of total sales were accounted for by four drugs in 1975, 1980 and 1985; five in 1990; seven drugs in 1995 and 2000; and six drugs in 2001 and 2002. CONCLUSIONS: The rapid growth in antidepressant prescribing that was characteristic of the early 1990s, and reflected the emergence of new classes of agents, did not continue into the late 1990s. Selective serotonin reuptake inhibitors now dominate antidepressant prescribing in Australia.

Length of therapy with selective serotonin reuptake inhibitors and tricyclic antidepressants in Australia.

OBJECTIVE: To investigate the proportion of patients starting on either selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) who continued treatment for a period consistent with recommended guidelines for major depression, that is at least 6 months. METHOD: Cohort study using a national dispensing claims database involving patients eligible for social security entitlements in Australia. Two 'new user' cohorts were established of patients who were supplied a prescription for either an SSRI (6026) or a TCA (4158) in the first week of April 2000 and who had not received a prescription for any antidepressant in the preceding three months. The main outcome measure was the proportion of patients who were still having any SSRI or TCA prescription, respectively, dispensed between 6 and 8 months after initiation. Additionally, for patients starting on either a leading SSRI (sertraline) or TCA (dothiepin), the proportions of those that remained on these drugs or had changed to other antidepressants were determined. The dispensing data are not linked to reason for prescribing in the national dataset. RESULTS: 2267 SSRI 'new users' (38%) were still receiving SSRIs 6-8 months later, compared with 1269 (31%) of the 4158 TCA 'new users' (p < 0.001). The difference between the groups occurred early, by the 2-4 month time interval. 1038 (41%) of patients starting on the individual SSRI and 385 (38%) of patients starting on the individual TCA were receiving some type of antidepressant therapy at 6-8 months, with no significant difference (p = 0.6) in the proportions that had changed to another antidepressant. CONCLUSIONS: In 2000, only 40% of patients started on an antidepressant continued to be prescribed some antidepressant therapy 6-8 months later. Patients were more likely to continue on SSRIs as a class than on TCAs and the difference in continuation between these two classes occurred within the first 2 months of therapy. However, patients starting on an individual SSRI or TCA were equally likely to change to another antidepressant.

Changes in fatalities due to overdose of anxiolytic and sedative drugs in the UK (1983-1999).

OBJECTIVE: To establish the frequency with which anxiolytic and sedative drugs result in fatal poisonings and to examine longitudinal changes in poisoning deaths. METHOD: The number of fatal poisonings between 1983 and 1999 in England, Scotland and Wales due to a single anxiolytic or sedative drug was obtained from the Department of Health in the UK. This was divided by the number of prescriptions for these drugs in England and Scotland to derive a fatal toxicity index (FTI) of deaths per million prescriptions. RESULTS: Chloral hydrate, clomethiazole, barbiturates, and related sedatives had much higher FTIs than benzodiazepines, buspirone, zolpidem and zopiclone. There has been a substantial reduction in the annual number of deaths from sedative drug poisoning between 1983 and 1999. This has been due to a sustained reduction in prescriptions for high toxicity drugs and more recently a major reduction in temazepam deaths that coincided with the withdrawal of gelatin capsule formulations. CONCLUSION: Deaths would be expected to be further reduced if there were reduced prescriptions of high toxicity drugs--and the continuing need for short-acting barbiturates, clomethiazole and chloral hydrate should be questioned.

Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis.

OBJECTIVE: To examine the association between trends in antidepressant prescribing and suicide rates in Australia for 1991-2000. DESIGN: Analysis of databases of suicide and rates of antidepressant prescribing according to age and sex. SETTING: Australian Bureau of Statistics data, sales data from the Australian pharmaceutical industry, prescribing data in general practice. SUBJECTS: Men and women aged 15 years and over in 10 year age groups. MAIN OUTCOME MEASURES: Trends in suicide rates and trends in antidepressant prescribing. Association measured by Spearman's rank correlations. RESULTS: While overall national rates of suicide did not fall significantly, incidence decreased in older men and women and increased in younger adults. In both men (r(s)=-0.91; P<0.01) and women (r(s)=-0.76; P<0.05) the higher the exposure to antidepressants the larger the decline in rate of suicide. CONCLUSIONS: Changes in suicide rates and exposure to antidepressants in Australia for 1991-2000 are significantly associated. This effect is most apparent in older age groups, in which rates of suicide decreased substantially in association with exposure to antidepressants. The increase in antidepressant prescribing may be a proxy marker for improved overall management of depression. If so, increased prescribing of selective serotonin reuptake inhibitors in general practice may have produced a quantifiable benefit in population mental health.

Use of antidepressants by general practitioners and psychiatrists in Australia.

OBJECTIVE: To examine the antidepressant prescribing patterns of psychiatrists and general practitioners (GPs) in Australia, focusing specifically on: the prescribed daily dose, the relative proportions (from subsidized dispensing data) of prescriptions written, and how these proportions change over time for a newly listed antidepressant drug (using paroxetine as an example). METHOD: Retrospective analyses of subsidized claims data (comprising nearly 90% of the community supply of antidepressants) and prescriber surveys. RESULTS: General practitioners prescribe 86% of subsidized antidepressants in Australia. Almost three-quarters of the antidepressant prescriptions prescribed in primary care management are also initiated by a GP. Psychiatrists prescribed higher doses than general practitioners for all the antidepressants examined. For paroxetine, a higher than average proportion of scripts were written by psychiatrists when the drug was initially available and it only reached the GP/psychiatrist split seen with an established drug in the same therapeutic class (fluoxetine) four years after marketing. The most prominent type of depression that GPs believed they were treating was 'chronic mild depression', which contrasts with the subsidized indication for all newer antidepressant classes of 'major depressive disorders'. CONCLUSIONS: General practitioners are the major providers of treatment for depression in Australia. When writing prescriptions for tricyclic antidepressants GPs use doses lower than those recommended for major depression, however, most management in primary care is not for conditions regarded by the GP as major depression. A significant number of prescriptions for the newer antidepressants may not accord with the Pharmaceutical Benefits Scheme (PBS) restrictions for use.

Non-antiarrhythmic drugs prolonging the QT interval: considerable use in seven countries.

AIMS: Many drugs belonging to different therapeutic classes appear to share a potentially fatal side-effect: ventricular tachyarrhythmias associated with QT prolongation. The aim of this study was to assess the relevance and the magnitude of the problem in seven countries by grouping all nonantiarrhythmic drugs according to the type of evidence on QT prolongation and analysing their sales data. METHODS: We divided all nonantiarrhythmic QT-prolonging agents into the following categories (in increasing order of clinical relevance): group A, drugs with published clinical or preclinical evidence on QT prolongation or with relevant official warnings; group B, drugs with published clinical or preclinical evidence; group C, drugs with published clinical evidence; group D, drug with published clinical evidence on torsades de pointes or ventricular arrhythmias associated with QT prolongation; group E, drugs belonging to group D with official warnings. We retrieved 1998 sales data from community pharmacies in seven countries (Australia, Denmark, England, Germany, Greece, Italy and Sweden). Data for individual agents were expressed as defined daily doses per 1000 inhabitants per day (DDD/1000/day). Overall use in each country was calculated for each drug group. Groups D and E were considered as the most clinically relevant. RESULTS: Among the 102 nonantiarrhythmic agents meeting at least one of the inclusion criteria, 33 drugs had sales data > or =1 DDD/1000/day and 71 drugs had a use > or =0.1 DDD/1000/day in at least one country. Among the 37 nonantiarrhythmic agents with published reports of ventricular arrhythmias associated with QT prolongation, 12 compounds had sales data > or =1 DDD/1000/day. Total consumption in each country ranged: from 51.9 to 94.7 DDD/1000/day for group A; from 51.6 to 92.7 DDD/1000/day for group B; from 37.1 to 76.6 DDD/1000/day for group C; from 12.9 to 29.1 DDD/1000/day for group D; and from 5.8 to 15.3 DDD/1000/day for group E. CONCLUSIONS: In spite of wide variations in the sales of individual agents, the overall extent of use of nonantiarrhythmic QT-prolonging drugs was of the same order of magnitude in all countries. The significant use of drugs belonging to categories D and E should prompt careful risk/benefit assessment of each agent.