Alasdair G. Rooney

Depression in Cerebral Glioma Patients: A Systematic Review of Observational Studies

BACKGROUND Depression is a common and important complication of primary cerebral glioma. However, observational studies of this relationship have not been systematically reviewed. METHODS We searched MEDLINE, EMBASE, and PsycINFO for all English-language cross-sectional, case-control, and cohort studies of depression in adults with primary glioma published between January 1, 1980, and September 16, 2009. We identified 42 eligible studies that recruited 4089 individual glioma patients. We conducted a narrative review of these studies regarding the heterogeneity in diagnostic methods, the frequency of depression and its clinical associations, and the quality of study reporting. RESULTS Most studies of depression in adults with glioma were small, cross-sectional, or retrospective. Depression was most often measured using the Hospital Anxiety and Depression Scale (HADS; n = 10 studies). The Beck Depression Inventory, another frequently used screening instrument, returned a higher frequency of depression (median = 39%, range = 38%-42%) than the Hospital Anxiety and Depression Scale (median = 16%, range = 0%-21%). At clinical interview, the median frequency of depression in glioma was 15% (range = 6%-28%). Depression was consistently associated with reduced physical function, cognitive impairment, and reduced quality of life. It may be associated with reduced survival, although evidence for this association was modest. There was an absence of clear associations between depression and many tumor-related variables. Few observational studies examined the treatment of depression in glioma patients. Multivariable analyses were rare, and study reporting was of variable quality. CONCLUSIONS In glioma, mild to moderate depressive symptoms may only rarely be due to tumor-associated structural or functional disruption of neuronal emotional networks. Improved methodological reporting would help clinicians better evaluate future studies, and facilitate improved evidence-based care of depressed glioma patients.

Frequency, Clinical Associations, and Longitudinal Course of Major Depressive Disorder in Adults With Cerebral Glioma

PURPOSE There is a need for high-quality evidence regarding the frequency, independent clinical associations, and longitudinal course of depression in patients with cerebral glioma. PATIENTS AND METHODS This was a twin-center, prospective, observational cohort study with 6-month follow-up. Consenting adults with a new diagnosis of cerebral glioma received the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition to diagnose major depressive disorder (MDD). Interviews occurred shortly after the start of radiotherapy (T1), with follow-up interviews 3 months later (T2) and 6 months later (T3). Independent associations between MDD and clinical variables were analyzed using logistic regression. RESULTS One hundred fifty-five patients participated. The frequency of MDD was 13.5% ± 5.4% at T1 (n = 155); 14.8% ± 6.7% at T2 (n = 108); and 6.8% ± 5.3% at T3 (n = 88). Overall, 32 individuals were diagnosed with MDD during the study period (20.6% ± 6.4%). Inter-rater diagnostic agreement for MDD was good (κ = 0.81; 95% CI, 0.60 to 1.00). Independent predictors of MDD were functional impairment (odds ratio, 3.9; 95% CI, 1.5 to 10.8) and a previous history of depression (odds ratio, 2.7; 95% CI, 0.99 to 7.3). MDD persisted for at least 3 months in half of the patients with adequate follow-up, but many depressed patients also dropped out of the study as a result of clinical deterioration. CONCLUSION In this longitudinal study, one in five patients with glioma developed clinical depression in the 6 months after starting radiotherapy. Patients with functional impairment or previous depression were at higher risk. MDD often persisted for at least 3 months. Clinicians should seek and treat depression in adults with glioma.

Depression in glioma: a primer for clinicians and researchers

Depression is one of the leading causes of global disability, and a considerable hidden morbidity among patients with glioma. In this narrative review, we summarise what is currently known about depression in glioma, the main unanswered questions and the types of studies that should be prioritised in order to find out. We conclude by calling for a prospective Phase II study of antidepressants in depressed glioma patients, to test methodologies for a multicentre randomised controlled trial.

The frequency, longitudinal course, clinical associations, and causes of emotional distress during primary treatment of cerebral glioma

BACKGROUND Relatively little is known about the frequency, longitudinal course, independent associations, and reported causes of emotional distress in adults with primary cerebral glioma. We aimed to describe these features in an observational study. METHODS This was a twin-center prospective cohort study. Eligible adults were those with a new histological diagnosis of glioma who were receiving active management. Distress was measured using the National Comprehensive Cancer Network Distress Thermometer and problem checklist. Subjects were sampled at 3 timepoints: T1 (shortly after starting chemo/radiotherapy), T2 (3 months later), and T3 (6 months later). RESULTS T1 n = 154; T2 n = 103; T3 n = 83. Significant distress was present in 36.4 ± 7.6% at T1, 35.9 ± 9.3% at T2, and 33.7 ± 10.2% at T3. Longitudinally, subjects with high distress at T1 (median Distress Thermometer score = 8; interquartile range [IQR] 7-9) remained highly distressed on follow-up (T2 median = 8, IQR 6-8; T3 median = 7, IQR 5-8) (Friedman test P = .304). Younger age, functional impairment, and concurrent major depressive disorder were independently associated with high distress (logistic regression χ(2) for model = 39.882, P < .001, R(2) = 0.312). The most frequently reported causes of distress were worry, fatigue, sleep difficulties, and sadness. Emotional difficulties were among the most common causes of distress at all 3 timepoints. CONCLUSIONS At each timepoint, one-third of patients reported significant emotional distress, which persisted during follow-up among those initially highly distressed. Young, functionally impaired, and depressed glioma patients may particularly benefit from increased support.

European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma

Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning.

Psychiatric symptoms in glioma patients: from diagnosis to management

Patients with primary intrinsic brain tumors can experience neurological, cognitive, and psychiatric symptoms that greatly affect daily life. In this review, we focus on changes in personality and behavior, mood issues, hallucinations, and psychosis, because these are either difficult to recognize, to treat, or are understudied in scientific literature. Neurobehavioral symptoms are common, often multiple, and causation can be multifactorial. Although different symptoms sometimes require a different treatment approach, we advise a comprehensive treatment approach, including pharmacological treatment and/or psychotherapy where appropriate. Further research is needed to obtain a better estimate of the prevalence of psychiatric symptoms in glioma patients, and the extent to which these affect everyday functioning and family life.

VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

Significance Generation of new neurons is maintained in the adult hippocampus throughout life. The process, which is driven by an exhaustible reservoir of neuronal stem cells (NSCs), greatly declines with age, however. We show that even a short, episodic exposure to the angiogenic factor VEGF and a resultant ramification/rejuvenation of the vasculature within the stem cell microenvironment (“niche”) is sufficient for neurogenesis to proceed at a markedly elevated rate for months later without accelerating the rate of NSC depletion. Importantly, this manipulation culminates in marked attenuation of age-dependent neurogenic decline. Long-term neurogenic enhancement via VEGF preconditioning was found to be associated with extensive NSC morphological remodeling resembling a “juvenile” pattern of NSC and blood vessel engagements. Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal “juvenile” NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an “aged” systemic milieu.

Female gender is not a proven risk factor for depression in glioma

To the Editor:We read Litofsky and Resnick’s timely and useful reviewof depression in brain tumour patients with interest [1]. Theauthors identified screening for depression as an issuerequiring future study. Because screening is often targetedat high-risk groups, it is important to study the risk factorsfor depression in brain tumour patients.The authors state that female gender is a risk factor fordepression in glioma. It is true that some groups have foundwomen with brain tumours to be more likely than men tobecome depressed [2, 3]. However other researchers havenot, including one of the authors of the review [4–6].We sent a questionnaire to the GP of each glioma patienton our hospital database (Edinburgh, UK), asking whethertheir patient had suffered depression both before and sincethe diagnosis of glioma. The diagnosis of depression wasbased on the clinical judgement of each GP. Response ratewas 68% (100/147; 55% male). A pre-glioma (past medi-cal) history of depression was significantly more likely inwomen (12/45 women compared with 3/55 men;P = 0.004, Fisher’s Exact Test). However following gli-oma presentation the sex difference in depression disap-peared and men were equally as likely as women toexperience depression (12/55 and 12/45 respectively;P = 0.64).Female gender is not a proven risk factor for depressionin glioma. Since general population surveys consistentlyreport that depression is twice as common in women [7],studies reporting a more equal sex distribution fordepression in brain tumours may even suggest a relativelyincreased risk for men.We agree that depression in glioma is a fertile field forresearch. For now we suggest that men and women withglioma should be considered at equal risk of developingdepression, and that efforts should therefore be made toinclude them equally in any proposed screeningprogrammes.References

SSRIs may (or may not) be a safe treatment for depression in GBM.

To the Editor: Studies of the pharmacologic treatment of depression in glioma are rare and Caudill et al make an important contribution to this field. However, their conclusion that ‘‘treatment of depression with selective serotonin reuptake inhibitors (SSRIs) in patients with glioblastoma multiforme (GBM) is safe’’ is premature. The authors assumed that clinically significant depressive symptoms were present only in those patients receiving an SSRI during the study period. Yet, depression is under-recognized in cancer patients. Some patients receiving no SSRI in this retrospective study may also have been depressed. This possibility is supported by at least 2 patterns in the data. Firstly, patients receiving an SSRI had a similar Recursive Partitioning Analysis class—incorporating functional status—to those receiving no SSRI. This similarity in is surprising because depression is usually associated with functional impairment in glioma. A plausible explanation would be that some unrecognized depressed (and functionally impaired) patients were included in the ‘‘no SSRI’’ group. Secondly, mortality was higher in patients receiving no SSRI. As depression is independently associated with mortality in cancer patients, the observed higher mortality could also have been mediated by unrecognized depression in the no SSRI group. If some depression was unrecognized, then the sample of GBM patients receiving SSRIs may not have been representative of the wider population of depressed GBM patients. Particularly in a retrospective study, it would be dicult to generalize logically to the conclusion that SSRIs are a safe treatment for depression in GBM. The theoretical risk of precipitating epilepsy warrants caution. Patients with glioma are at very high risk of seizures. Most, if not all, SSRI licensing studies excluded glioma patients. The risk of SSRI-associated epilepsy in glioma is far from clear. It is reassuring that Caudill et al found GBM patients taking an SSRI to have no markedly increased risk of epilepsy. Yet, this finding was based solely on the available clinical record. The number and nature of seizures was not presented by the authors. The rigor with which epilepsy was sought and confirmed by treating clinicians is unknown. The study lacked a single-minded focus on studying epilepsy. The authors alluded to diculty identifying adverse events in a retrospective study design. Although the data is encouraging, a cautious interpretation is reasonable. With regard to other potential side-eects, we note that the 2 most frequently prescribed SSRIs were sertraline and citalopram. These drugs have relatively few interactions with the cytochrome (CY) P450 system. However, other popular SSRIs including fluoxetine and paroxetine inhibit the CYP450 system to a greater extent. Symptoms of toxicity from chemotherapy or antiepileptic drugs might theoretically emerge with greater CYP450 inhibition in GBM patients. This possibility could not be excluded in the relatively small sample of patients taking these drugs. The precise timings, durations, and dosages of any SSRI treatments given in the study also were not stated, limiting clinical applicability. Caudill et al have conducted a novel study highlighting a neglected and important area. However, the safety of SSRIs in depressed GBM patients remains largely unknown. Prospective studies are required to evaluate this topic further. Meanwhile, clinicians managing depression in GBM could discuss the potential risk and benefit of dierent treatments with the patient, prescribing SSRIs where judged necessary with caution and close follow-up. Alasdair Rooney, MBChB Robin Grant, MD Edinburgh Centre for Neuro-Oncology, Western General Hospital, Edinburgh, UK

Probability of major depression diagnostic classification using semi-structured versus fully structured diagnostic interviews

BACKGROUND Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics. METHOD Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit. RESULTS A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15-3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98-10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) (OR = 0.96; 95% CI = 0.56-1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26-0.97). CONCLUSIONS The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.