Real-time drug testing of paediatric diffuse midline glioma to support clinical decision making: The Zurich DIPG/DMG centre experience.

BACKGROUND: Children diagnosed with diffuse midline gliomas (DMG) have an extremely poor overall survival: 9-12 months from diagnosis with currently no curative treatment options. Given DMG molecular heterogeneity, surgical biopsies are needed for molecular profiling and as part of enrolment into molecular-based and precision medicine type clinical interventions. In this study, we describe the results of real time profiling and drug testing at the diffuse intrinsic pontine glioma/DMG Research Centre at University Children's Hospital Zurich. METHOD: Biopsies were taken using a frame based stereotactic robot system (NeuroMate®, Renishaw) at University Children's Hospital Zurich. Tissue samples were evaluated to confirm diagnosis by H3K27M and H3K27 trimethylation loss. Genomic analyses were done using a variety of platforms (INFORM, Oncomine, UCSF500 gene panel). Cell lines were developed by mechanical tissue dissociation and verified by either sequencing or immunofluorescence staining confirming H3K27M mutation and used afterwards for drug testing. RESULTS: Twenty-five robot-assisted primary biopsies were successfully performed. Median hospital stay was 2 days (range 1-4 days). Nine low-passage patient-derived cells were developed, whereas 8 cell lines were used to inform response to clinically relevant drugs. Genome and RNA expression were used to further guide treatment strategies with targeted agents such as dual PI3K/mTOR inhibitor paxalisib. CONCLUSION: We established a systematic workflow for safe, robot-assisted brainstem biopsies and in-house tissue processing, followed by real-time drug testing. This provides valuable insights into tumour prognostic and individual treatment strategies targeting relevant vulnerabilities in these tumours in a clinically meaningful time frame.

Whole-spine dynamic magnetic resonance study of contortionists: anatomy and pathology.

OBJECT: Whole-spine magnetic resonance (MR) images were obtained using a cylindrical 3-T MR imaging system in 5 contortionists to assess the pathological changes possibly associated with the practice of contortion. Whole-spine dynamic MR images were obtained using a 1-T open MR imaging system in 2 of these contortionists with the purpose of defining the range of motion (ROM) achieved during extreme contortion. The range of spinal motion in this unique population was then quantified. METHODS: The study included 5 female contortionists 20-49 years of age. Imaging was performed using open 1-T and cylindrical 3-T high-field MR imaging systems. Data were viewed and analyzed with DICOM-compliant tools. Real-time, dynamic, and standard MR imaging allowed for quantification of the contortionists' ROM. RESULTS: There was a difference of 238 degrees between full spinal extension and full flexion. Three of the 5 contortionists had 4 anterosuperior limbus vertebrae at T-11 and the upper lumbar levels. CONCLUSIONS: Whole-spine dynamic MR imaging is a valuable tool for the evaluation of the extreme ROM in contortionists, allowing for the quantification of extreme mobility. The limbus fractures present in 3 of the 5 contortionists is postulated to be due to avulsion on hyperextension. Future research may open the use of whole-spine dynamic MR imaging into such areas as pain management and traumatic spinal injuries.

Predicting recovery from episodes of major depression.

BACKGROUND: This study examined psychosocial functioning as a predictor of recovery from episodes of unipolar major depression. METHODS: 231 subjects diagnosed with major depressive disorder according to Research Diagnostic Criteria were prospectively followed for up to 20 years as part of the NIMH Collaborative Depression Study. The association between psychosocial functioning and recovery from episodes of unipolar major depression was analyzed with a mixed-effects logistic regression model which controlled for cumulative morbidity, defined as the amount of time ill with major depression during prospective follow-up. Recovery was defined as at least eight consecutive weeks with either no symptoms of major depression, or only one or two symptoms at a mild level of severity. RESULTS: In the mixed-effects model, a one standard deviation increase in psychosocial impairment was significantly associated with a 22% decrease in the likelihood of subsequent recovery from an episode of major depression (OR=0.78, 95% CI: 0.74-0.82, Z=-3.17, p<0.002). Also, a one standard deviation increase in cumulative morbidity was significantly associated with a 61% decrease in the probability of recovery (OR=0.3899, 95% CI: 0.3894-0.3903, Z=-7.21, p<0.001). LIMITATIONS: The generalizability of the study is limited in so far as subjects were recruited as they sought treatment at academic medical centers. The analyses examined the relationship between psychosocial functioning and recovery from major depression, and did not include episodes of minor depression. Furthermore, this was an observational study and the investigators did not control treatment. CONCLUSIONS: Assessment of psychosocial impairment may help identify patients less likely to recover from an episode of major depression.

The naturalistic course of unipolar major depression in the absence of somatic therapy.

The goal of the study was to describe the naturalistic course of unipolar major depression in subjects not receiving somatic therapy for their depressive illness. Affectively ill individuals were recruited into the Collaborative Depression Study and followed prospectively for up to 15 years. One hundred thirty subjects who recovered from their intake episode of major depression subsequently experienced a recurrence that went untreated for at least 4 weeks following onset of the recurrence. The duration of the recurrent episode was examined using survival analytic techniques. Of the 130 subjects, 46 obtained somatic therapy at some time during the course of their depressive illness, while 84 subjects received no somatic therapy throughout their entire depressive episode. Survival analysis, which accounts for these 46 individuals by censoring their episodes at the time treatment was obtained, yielded a median time to recovery of 23 weeks. In the subsample of 84 subjects whose depressive illness went untreated from its inception through its resolution, the median time to recovery was 13 weeks. These results suggest that there is a high rate of recovery in individuals not receiving somatic treatment of their depressive illness, particularly in the first 3 months of an episode. Because treatment-seeking behavior is known to be associated with a worse prognosis, 23 weeks probably represents a lower-limit approximation of the median duration of an untreated depressive episode.

Sertraline treatment of co-occurring alcohol dependence and major depression.

BACKGROUND: Major depressive disorder occurs commonly in association with alcohol dependence, both in clinical samples and in the community. Efforts to treat major depressive disorder in alcoholics with antidepressants have yielded mixed results. This multicenter, double-blind, placebo-controlled trial of sertraline was designed to address many of the potential methodological shortcomings of studies of co-occurring disorders. METHOD: Following a 1-week, single-blind, placebo lead-in period, 328 patients with co-occurring major depressive disorder and alcohol dependence were randomly assigned to receive 10 weeks of treatment with sertraline (at a maximum dose of 200 mg/d) or matching placebo. Randomization was stratified, based on whether initially elevated scores on the 17-item Hamilton Depression Rating Scale declined with cessation of heavy drinking, resulting in a sample of 189 patients with Hamilton Depression Rating Scale scores > or =17 (group A) and 139 patients with Hamilton Depression Rating Scale scores < or =16 (group B). RESULTS: Both depressive symptoms and alcohol consumption decreased substantially over time in both groups. There were no reliable medication group differences on depressive symptoms or drinking behavior in either group A or B patients. CONCLUSION: Despite careful attention to methodological considerations, this study does not provide consistent support for the use of sertraline to treat co-occurring major depressive disorder and alcohol dependence. The high rate of response among placebo-treated patients may help to explain these findings. Further research is needed to identify efficacious treatments for patients with these commonly co-occurring disorders.

Long-term use of benzodiazepines in participants with comorbid anxiety and alcohol use disorders.

BACKGROUND: Although the only widely accepted role for benzodiazepines in alcohol dependence is the treatment of withdrawal syndromes, they are frequently prescribed outside of this clinical setting. There is little empirical evidence to guide the rational use of benzodiazepines in the common clinical situation where anxiety disorders are comorbid with alcohol use disorders (AUD). Since January 1989, the Harvard Anxiety Research Program has naturalistically monitored the prospective clinical course of people with anxiety disorders, some of whom had a history of AUD. Earlier research showed that the use of benzodiazepines was not significantly associated with the presence or absence of a history of an AUD over the first year of follow-up. This report extends that investigation. METHODS: Using standard parametric analytic methods, patterns of benzodiazepine use (routinely prescribed medication and as-needed [PRN] use) among participants receiving benzodiazepine treatment was prospectively examined over the course of 12 years. Differences in benzodiazepine usage patterns were examined in each year of follow-up between participants who did (n=120) and did not (n=425) have a new episode of AUD. Using proportional hazards regression analysis, benzodiazepine usage levels were examined as predictors of recovery and recurrence of AUD. Additionally, random-effects regression analyses were used to examine the patterns of benzodiazepine use before and after the onset of a prospectively observed episode of AUD. RESULTS: Benzodiazepine usage levels remained stable for the full sample over the course of the 12 years. Benzodiazepine use did not distinguish participants who had a new AUD from those who did not. Over the 12 years of follow-up, participants who had an AUD used more PRN medication in years five to eight. This difference reached statistical significance but was not clinically significant. Benzodiazepine usage levels did not predict recovery or recurrence in AUD subjects. Neither the total dose nor the PRN usage of benzodiazepines was significantly associated with the onset of AUD, but when combined into a measure of any benzodiazepine use, a relationship between increased use and the onset of AUD emerged. CONCLUSIONS: For participants in the Harvard Anxiety Research Program with comorbid alcohol dependence and anxiety disorders, there was little association between the use of benzodiazepines and the occurrence of a new AUD. Neither was there a temporal relationship between the use of benzodiazepines and the onset of a new AUD. Whether or not this finding extends to a broader patient population or a group of people who present to addictions treatment awaits further investigation.

Tachyphylaxis in unipolar major depressive disorder.

BACKGROUND: Major depressive disorder is usually a recurring illness, and maintenance treatment is used to forestall or prevent recurrent episodes of depression. This study describes recurrence of major depression despite maintenance pharmacotherapy, termed tachyphylaxis. METHOD: The study sample consisted of 103 subjects who participated in the NIMH Collaborative Depression Study, a multicenter longitudinal observational study of the mood disorders. Subjects diagnosed with unipolar major depressive disorder according to Research Diagnostic Criteria were enrolled from 1978-1981 and prospectively followed for up to 20 years. As an observational study, treatment was recorded but not controlled by anyone connected with the study. Subjects were selected for the present study if at some point during follow-up they received antidepressant medication for treatment of an episode of major depressive disorder, recovered from this episode, and subsequently received maintenance pharmacotherapy. Some subjects were successfully treated for multiple episodes of major depressive disorder and then received maintenance medication after each of these episodes, resulting in multiple maintenance treatment intervals. Data were collected using the Longitudinal Interval Follow-Up Evaluation, and mixed-effects logistic regression was used to test the association of sociodemographic and clinical variables with tachyphylaxis. RESULTS: For the 103 subjects, there were 171 maintenance treatment intervals in which a subject received maintenance pharmacotherapy after having recovered from an episode of major depressive disorder. The median duration of maintenance treatment was 20 weeks. Tachyphylaxis occurred during 43 (25%) of these 171 maintenance treatment intervals. The subtype of melancholic (endogenous) major depressive disorder significantly elevated the risk of tachyphylaxis during the subsequent maintenance treatment interval. CONCLUSIONS: Despite the use of maintenance pharmacotherapy, major depression recurs in a considerable number of patients. Improved prophylaxis for these patients requires other treatment strategies based upon a greater understanding of recurrence.

Psychosocial impairment and recurrence of major depression.

Major depressive disorder is often marked by multiple recurrences. Unfortunately, it is difficult to predict specifically which patients will suffer a recurrence. This study examined whether psychosocial impairment is a risk factor for recurrence. A total of 290 subjects with unipolar major depressive disorder according to Research Diagnostic Criteria (RDC) were prospectively followed for up to 15 years as part of the Collaborative Depression Study (CDS), a multicenter longitudinal observational study of the mood disorders. Follow-up data on course of illness and psychosocial functioning were collected with the Longitudinal Interval Follow-up Evaluation (LIFE). The association of psychosocial impairment with recurrence of major depression was examined with mixed-effects logistic regression. The mean (SD) score for psychosocial functioning during recovery from an episode of major depression was 9.0 (2.7), with a possible range of 4 (no impairment) to 20 (severe impairment). For euthymic subjects who recovered from an episode of major depression, elevated psychosocial impairment was significantly associated with subsequent recurrence of major depression, with an odds ratio of 1.12 (95% confidence interval [CI], 1.06 to 1.19). The odds ratio of 1.12 indicates that for each 1-point increase in the functional impairment score, the risk of recurrence increases by about 12%. In patients who have recovered from an episode of major depression, the presence of psychosocial impairment may help identify who is at increased risk of recurrence.

Motivational enhancement and coping skills training for cocaine abusers: effects on substance use outcomes.

AIMS: This clinical trial investigated effects of motivational enhancement treatment (MET) and group coping-skills training (CST) tailored for cocaine dependence. Effects of MET were hypothesized to be greater with CST and for less motivated patients. DESIGN AND INTERVENTIONS: A 2 x 2 design investigated two individual sessions of MET compared to meditation-relaxation (MRT), followed by four group sessions of CST versus drug education (ED), as daily adjuncts to intensive treatment. SETTING: The substance abuse program provided full-day treatment with a learning-theory and 12-Step orientation. PARTICIPANTS: Cocaine-dependent patients were recruited. MEASUREMENTS: Assessment included treatment retention; change in cocaine-related urge, self-efficacy, pros and cons, and motivation; substance use and problems during 12-month follow-up. Findings Of 165 patients, follow-up status is known for 90% (n = 149). Patients in MET with low initial motivation to change reported less cocaine and alcohol relapse and use days and fewer alcohol problems than MET patients with higher initial motivation. MET produced more employment improvement than MRT, with no other significant benefit for MET. Patients with higher motivation had more cocaine use and alcohol problems after MET than MRT. Group CST reduced cocaine and alcohol use during follow-up for women only and reduced alcohol relapse for men and women. CONCLUSIONS: MET is more beneficial for patients with lower initial motivation than for patients with high initial motivation. CST reduced cocaine and alcohol use for women only and reduced alcohol relapses, in contrast to results with lengthier individual CST.

Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema.

Hypotheses about relationships between changes in membrane lipids and mental illness have focused primarily on three long-chain polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Membrane deficiencies of these fatty acids have been reported in schizophrenia (AA, EPA, and DHA) and in depression (EPA and DHA). Long-chain fatty acid-CoA ligase type 4 (FACL4; MIM 300157) is a key enzyme involved in the metabolism of AA, EPA, and DHA. FACL4 selectively esterifies these fatty acids with co-enzyme A, forming acyl-co-A, which can then be incorporated into membrane phospholipid. We used niacin-induced dermal erythema as one index of AA metabolism to identify a common C to T single nucleotide polymorphism (SNP) in the first intron of the FACL4 gene (Xq22.3), which is associated with enhanced dermal erythema in both schizophrenia and control subjects. Male subjects with the T0 genotype showed greater dermal erythema following topical application of methylnicotinate, suggesting that this polymorphism may be in linkage disequilibrium with a functional polymorphism of the FACL4 gene that modulates re-sequestration of agonist-released free AA. We also examined the allele frequency of this polymorphism in 555 European-Americans (EA), including 229 control subjects, 198 subjects with major depression, 58 with schizophrenia or schizoaffective disorder, and 70 with alcohol dependence without co-morbid psychiatric illness. We observed a significant excess of the T allele in subjects with major depression, as compared with controls (49% vs. 38%; P = 0.003) and a non-significant excess of the T allele in schizophrenia (44%; P = 0.29). The allele frequency for subjects with alcohol dependence did not differ from controls.

The course of depression in elderly patients.

OBJECTIVE: Studies on the course of major depressive disorder (MDD) among elderly persons are limited to short periods of follow-up, seldom provide comparisons with younger cohorts, and raise other methodological concerns. METHODS: Utilizing 15 years of prospective data from the NIMH Collaborative Depression Study, the authors examined the index episode of MDD and the time until first observed recurrence in those who recovered for subjects in four age-groups defined by age at intake: 17-30, 31-50, 51-64, and 65-79 years. Assessments were conducted every 6 months for 5 years and annually thereafter. Survival analysis examined time until recovery and time to first recurrence. RESULTS: Median time-to-recovery was similar for the four groups. Median time-to-first recurrence was significantly shorter for oldest versus the 51-64-year-old group but not the two other groups. The oldest age-group was distinguished from the younger groups by being more likely to be divorced/widowed/separated, to have primary depression, and to have a history of medical illness, particularly cardiovascular disease or cancer. There was no difference in the generally low levels of pharmacotherapy prescribed during the index episode or the subsequent well interval. CONCLUSIONS: Elderly patients with MDD may have a greater risk of recurrence than younger individuals. Low levels of treatment characterize the somatic treatment in all the study subjects, regardless of age-group.

Unipolar mania over the course of a 20-year follow-up study.

OBJECTIVE: Using data from a longitudinal study of the mood disorders, the investigators address the phenomenon of unipolar mania. METHOD: Subjects diagnosed as having Research Diagnostic Criteria mania at intake into the study were prospectively followed for up to 20 years. RESULTS: Twenty-seven subjects had the diagnosis of unipolar mania at the time they entered the study and had no history of major depression before enrolling in the study. Seven of these subjects did not suffer any episodes of major depression during the 15- to 20-year follow-up. CONCLUSIONS: These data support the diagnostic validity of unipolar mania.

The long-term course of rapid-cycling bipolar disorder.

BACKGROUND: Rapid cycling among patients with bipolar affective disorders is important because of its implications for long-term prognosis and for the use of antidepressants. To our knowledge, no prospective study has, as yet, described the course of this phenomenon beyond 5 years. METHODS: From 345 patients with bipolar I or bipolar II disorder followed up for a mean (SD) of 13.7 (6.1) years as part of the National Institute of Mental Health Collaborative Depression Study, 89 (25.8%) were identified who, during 1 or more years of follow-up, manifested a pattern that met DSM-IV criteria for rapid cycling. These patients were compared with the remaining bipolar patients by demographics, overall affective morbidity, morbidity during specific treatment conditions, and the likelihood of suicidal behavior. Analyses assessed whether the use of tricyclic antidepressants for depressive symptoms was associated with the persistence of rapid cycling or with tendencies to switch from depressive to manic or hypomanic phases. RESULTS: The 89 patients who showed a rapid cycling pattern were significantly more likely to have had an illness onset before 17 years of age and were more likely to make serious suicide attempts. In 4 of 5 cases, rapid cycling ended within 2 years of its onset. Resolutions were not associated with decreases in tricyclic antidepressant use. Throughout follow-up, patients prone to rapid cycling experienced more depressive morbidity than other bipolar patients, particularly when lithium carbonate was being used without tricyclic antidepressants. The use of these antidepressants was not more likely in the weeks preceding shifts from depression to mania or hypomania. CONCLUSIONS: These results indicate that bipolar patients who develop a rapid cycling pattern suffer substantial depressive morbidity and are at high risk for serious suicide attempts. These findings do not implicate tricyclic antidepressants or, by inference, serotonin reuptake inhibitors in the promotion of affective instability.

Alleles of a functional serotonin transporter promoter polymorphism are associated with major depression in alcoholics.

BACKGROUND: Serotonergic neurotransmission has been implicated in the pathogenesis of both alcohol dependence and mood disorders and may therefore be important in understanding the pathophysiology of comorbid alcohol dependence and major depression. Studies of the association of these disorders with a functional polymorphism in the promoter region of the gene encoding the serotonin transporter protein (locus SLC6A4) have yielded inconsistent results. Because the convergence of these disorders may provide a refined phenotype, we examined the association of serotonin (5-HT) transporter linked polymorphic region (5-HTTLPR) alleles to comorbid alcohol dependence and major depression. METHODS: A sample of 296 European American and 16 African American patients with comorbid alcohol dependence and major depression was recruited from treatment studies. The control group included 260 European Americans and 43 African Americans; all were screened to exclude the presence of a mood or substance use disorder. DNA isolated from whole blood was polymerase chain reaction-amplified, and genotypes were assigned on the basis of agarose gel size fractionation. RESULTS: The frequency of the short allele in the patient group was in the range of those previously reported for samples with unipolar depression but was significantly more common than among controls (short allele frequency of cases, 45.8%; controls, 39.8%; chi(2)(1) = 4.02; p = 0.045). CONCLUSIONS: With respect to the frequency of the short allele at the SLC6A4 locus (5-HTTLPR), major depression in alcoholics is similar to major depression in nonalcoholics. Further efforts to characterize depressed alcoholics and to examine genetic predictors of response to antidepressant treatment seem warranted.

A 20-year longitudinal observational study of somatic antidepressant treatment effectiveness.

OBJECTIVE: This observational study examined the effectiveness of somatic antidepressant treatments as administered in the community. METHOD: The study group consisted of 285 subjects with an intake diagnosis of major depressive disorder who had entered the National Institute of Mental Health Collaborative Depression Study as early as 1978, had at least one additional affective episode, and had been followed for up to 20 years, as recently as 1999. The characteristics that distinguished subjects receiving various levels of somatic antidepressant treatment were accounted for in what was called a propensity for treatment intensity model. The effectiveness of somatic antidepressant treatment during major affective episodes was then examined. RESULTS: Those who received higher levels of antidepressant treatment tended to have more prior episodes, more severe depressive symptoms, and more intensive somatic therapy during prior episodes and prior well intervals than those who received lower levels. Treatment effectiveness analyses that were stratified by propensity for treatment intensity demonstrated that those who received higher levels of antidepressant treatment were significantly more likely to recover from affective episodes. In contrast, those treated with lower levels were no more likely to recover than those who did not receive somatic treatment. CONCLUSIONS: Despite the indications of more severe depressive illness, those who received higher levels of somatic antidepressant treatment were more likely to recover from recurrent affective episodes. Results from this observational study extend the generalizability of reports from randomized clinical trials of antidepressants to a wider, more representative group of individuals who suffer from major depression.

Negative mood, depressive symptoms, and major depression after smoking cessation treatment in smokers with a history of major depressive disorder.

Negative mood, depressive symptoms, and major depressive episodes (MDEs) were examined in 179 smokers with a history of major depression in a trial comparing standard smoking cessation treatment to treatment incorporating cognitive-behavioral therapy for depression (CBT-D). Early lapses were associated with relatively large increases in negative mood on quit date. Mood improved in the 2 weeks after quit date among those returning to regular smoking but not among those smoking moderately. Continuous abstinence was associated with short- and long-term reductions in depressive symptoms. MDE incidence during follow-up was 15.3% and was not associated with abstinence. Unexpected was that CBT-D was associated with greater negative mood and depressive symptoms and increased MDE risk. Results suggest complex bidirectional associations between affect and smoking outcomes.

The prospectively observed course of illness among depressed patients who commit suicide.

OBJECTIVE: These analyses were conducted to describe the course of illness among patients with major affective disorders who commit suicide. METHOD: Twenty-nine patients who entered a long-term, high-intensity follow-up study of major affective disorders and who later committed suicide within 1 year of their last follow-up interview were individually matched to other patients by age, sex, the presence or absence of lifetime drug or alcohol abuse, time to last interview and polarity. Those who suicided were compared with their controls by depressive and substance abuse morbidity during follow-up, treatment resistance, treatment compliance, suicidal behavior and psychosocial adjustment. RESULTS: Among the various measures used to characterize the course of illness during a mean follow-up of 4.3 years, only those pertaining to suicidal behavior robustly separated the suicide group from their controls. Suicidal behavior in the remote past seemed as predictively important as suicidal behavior during follow-up. CONCLUSION: Of the various features monitored over time in patients with major affective disorder, suicidal behavior itself was the clearest correlate of risk for completed suicide.

Can temperament identify affectively ill patients who engage in lethal or near-lethal suicidal behavior? A 14-year prospective study.

Among affectively ill patients followed naturalistically for up to 14 years, 36 committed suicide, 120 attempted suicide, and 373 had no recorded suicide attempt. Comparing these three groups on clinical and intake personality revealed that suicide completed within 12 months was predicted by clinical but not personality variables, and suicide beyond 12 months was predicted by newly derived temperament factors, not clinical variables. Attempters and completers shared core characteristics: previous attempts, impulsivity, substance abuse, and psychic turmoil within a cycling/mixed bipolar disorder. Such temperament attributes as impulsivity and assertiveness were the best prospective predictors of completed suicides beyond 12 months with a sensitivity level of 74% and specificity level of 82%.