The prevalence and recognition of major depression among low-level aged care residents with and without cognitive impairment

Previous research has demonstrated a high level of depression in nursing homes. The current study was designed to determine the prevalence of depression, using a structured diagnostic interview, among older people with and without mild-moderate cognitive impairment residing in low-level care facilities. The results demonstrated that, consistent with previous research in nursing homes, 16.9% of older people were diagnosed with major depressive disorder. Less than half of these cases had been detected or treated. Individuals with moderate cognitive impairment were more likely to be depressed, but cognitive impairment did not appear to act as a strong impediment to the detection of depression by general practitioners. A low awareness of their use of antidepressant medications was demonstrated among older people prescribed this treatment, including those with normal cognitive function. Reasons for the poor recognition of depression among older people are discussed.

Investigating the Effects of Mifepristone (RU486) in the Behavioral, Hormonal and Central Responses to Acute Stress

Depression is associated with glucocorticoid hypersecretion, due to dysfunction of the hypothalamo-pituitary-adrenocorticol axis (HPA-axis). Because excess glucocorticoids are associated with depressive-like features in humans, glucocorticoid receptor antagonists are currently being tested for antidepressant efficacy in clinical trials. In the current study the hypothesis that mifepristone (RU486), a glucocorticoid receptor antagonist, would decrease the neuroendocrine and central HPA-axis responses to an acute stressor and attentuate depressive like behavior in an animal model of behavioral helplessness (forced swim test) was tested. Adult male rats were treated with 10 mglkg RU486 (subcutaneous) for five days and then exposed to a IO-minute forced swim test (FST), conducted in Plexiglas cylinders. FST sessions were videotaped for later analysis of behavioral immobility. Plasma ACTH and corticosterone CORT were measured at 15min and 90min after FST cessation. Animals were perfused and brains were collected for immunocytochemical assessment of c-Fos expression in the medial prefrontal cortex (mPFC), a brain region implicated in both depression and central control of the HPA axis. RU486 significantly decreased peak ACTH and CORT concentrations following FST exposure. In addition, glucocorticoid negative feedback was at1enuated in RU486-treated animals exposed to the FST. Exposure to FST alone induced c-FOS expression in the mPFC, as measured by the number of c-Fos positive neurons. Treatment with RU486 significantly increased the number of rnPFC c-Fos positive cell following FST exposure. The behavioral data obtained from FST paradigm, demonstrated that RU486 decreased immobility in the FST illustrating the potential efficacy of this drug as an antidepressant. Collectively these data suggest that RU486 dampens HPA-axis responses to stress, possibly by enhancing the excitability of stress-inhibitory neurons in the mPFC. This is particularly exciting, given the fact that this neural region is associated with decreased neural activity during depression in humans.

Developmental outcomes of children exposed to antidepressants in pregnancy

Objective: To examine the developmental outcomes in children exposed to antidepressants in utero and compare those to children not exposed to these medications
Method: A prospective case-controlled study of children exposed to antidepressants in pregnancy assessed 22 exposed and 19 not exposed children using the Bayley Scales of Infant Development, third edition. The control group was measured at a mean age of 23.09 (SD 3.82) months and the medicated group at 28.53 months (SD 6.22). Maternal variables were assessed using a purpose-designed questionnaire and the Beck Depression Inventory (II) in pregnancy and at three assessments in the postpartum.
Results: Children exposed to antidepressant medication in pregnancy scored lower on motor subscales in particular on fine motor scores than non-exposed children with a moderate effect size of Cohen ’ s d = 0.47 fi ne motor and Cohen ’ s d = 0.43 for gross motor. Due to lack of power these findings did not reach conventional criteria for statistical significance. There was no association found between maternal depression and neurodevelopment.
Conclusions: This finding of a possible effect from antidepressant exposure in pregnancy on children ’ s motor development is similar to the findings from a previous study. Future research is needed which assesses children at an older age using specific assessments of motor development.

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial

Background Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking.

Aims To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health.

Method A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D3 (cholecalciferol) orally or placebo every autumn/winter for 3–5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression–Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants.

Results In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups.

Conclusions The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D3 is a practical intervention to prevent depressive symptoms in older community-dwelling women.

Depression and pain : an overview

Background: Depression and pain are both burdensome ailments that affect a major proportion of the population. It is evident that depression and pain frequently coexist, with treatment and outcome implications.

Objective: To review the literature on the nature, prevalence and co-morbidity of depression and pain, the biological and psychological mechanisms involved and treatment options, thus presenting a broad overview of the current information available.

Methods: Relevant sources were identified from PubMed and Medline databases using a combination of keywords including depression, pain, prevalence, co-morbidity, biological and psychological mechanisms, serotonin (5-HT), norepinephrine (NE), hypothalamic-pituitary-adrenal (HPA) axis, amygdala, functional magnetic resonance imaging (fMRI), antidepressant and psychological therapy.

Results: It is evident from the research that depression and pain are common co-morbidities. Pain as a physical symptom of depression affects approximately 65% of patients, leading to less favourable outcomes and greater health care utilization. Moreover, depression is a common feature in chronic pain patients and can affect pain threshold and tolerance. Evidence from biological and psychological studies has revealed mechanisms that link chronic pain to depression. Several classes of anti-depressants and psychological interventions have been used successfully in the treatment of somatic symptoms of depression and for a variety of pain syndromes.

Conclusions: Pain and depression are linked by overlapping phenomenology, neurobiology and therapy. They are mutually interacting, and the interaction has significant treatment and outcome implications.

Bipolar II disorder : a review

Objectives: To review the current knowledge of bipolar II disorder.

Methods: Literature was reviewed after conducting a Medline search and a hand search of relevant literature.

Results: Bipolar II disorder is a common disorder, with a prevalence of approximately 3–5%. Distinct clinical features of bipolar II disorder have been described. The key to diagnosis is the recognition of past hypomania, while depression is the typical presenting feature of the illness. This is responsible for a significant rate of missed diagnosis, and consequent management according to unipolar guidelines. It is unclear if bipolar II disorder is over-represented amongst resistant depression populations and if abrupt offset of antidepressant action is a phenomenon over represented in bipolar II disorder, reflecting induction of predominantly depressive cycling. A few mood-stabilizer studies available provide provisional suggestion of utility. A supportive role for psychosocial therapies is suggested, however, there is a sparsity of published studies specific to bipolar II disorder cohorts. A small number of short-term antidepressant trials have suggested efficacy, however, compelling long-term maintenance data is absent.

Conclusions: An emerging literature on the specific clinical signature and management of the disorder exists, however, this is disproportionately small relative to the epidemiology and clinical significance of the disorder.

Antidepressants and suicidal thought

The association of antidepressants with suicidal thought in people aged up to 25 year is a thorny issue. Balancing risk with benefit must always be at the core of any decision to treat and when the risk is an increased risk of suicide then a balanced decision can be difficult to make. Some clinicians who have been successfully treating patients using antidepressants have felt skepticism with these studies, finding them to be not reflective of their personal clinical experience. It may be wondered by some whether highlighting the link between suicidal thoughts and antidepressants may paradoxically lead to an increase in suicide by reducing the number of cases treated, however there is no evidence that this has occurred.

The association between antidepressants and suicidal thought may be unpalatable, but as with all new research the only way it can be judged is by the evidence to support it. The weight of evidence to demonstrate the association between antidepressants and suicidal thought in young people is convincing although the risk is low, estimated at one case of emerging suicidal ideation or suicide attempt for every 143 pediatric patients treated [1]. This risk is too low to displace antidepressants as the first line of treatment for depression but is too high a risk to be ignored. The risk is also too low to be recognized based on clinical experience alone as it is low enough to be imperceptible amongst suicides which occur due to depressive illness independent of antidepressant treatment. Only large studies are sufficiently powered to detect suicidal thought associated with antidepressant treatment. Clearly further studies would be helpful, especially if they can help characterize those at greatest risk. This is why the study by Lucy Goldsmith and Joanna Moncrieff in this issue of Current Drug Safety is an important step towards improving our understanding of antidepressant safety. These researchers find a link between increased suicidal impulses and emotional blunting and emotional instability.

Treating clinicians are urged to monitor for risk of suicide after initiation of antidepressant treatment, typically more frequently for the first four weeks of treatment and as indicated thereafter. However, if there is no history of suicidal thought or attempt and the patient does not admit to suicidal thought, suicidality may be missed by the treating clinician, ending in tragedy. Studies that provide new insights into this serious problem may lead to improvements in the effectiveness of monitoring patients for suicide risk, ultimately leading to better outcomes for patients.

Olanzapine / fluoxetine combination for treatment resistant depression : efficacy and clinical utility

Antidepressant monotherapy is a first-line treatment for depression; however, not all sufferers will adequately respond to treatment. When treating a patient with treatment-resistant depression, the clinician needs to consider all factors which may contribute to an inadequate response to an antidepressant. These include accuracy of diagnosis and medication adherence, as well as the patient’s personality, lifestyle, life events and social circumstances. If it is determined that treatment resistance is due to failure of efficacy of antidepressant monotherapy, then an augmentation strategy using an atypical antipsychotic may be considered. Treatment using olanzapine/fluoxetine combination (OFC) is one of many options. Four randomized, acute-phase trials have suggested OFC is useful for reducing Montgomery–Åsberg Depression Rating Scale scores after inadequate response to antidepressant monotherapy. OFC has been useful at doses of olanzapine/fluoxetine 6/25, 6/50, 12/25 and 12/50 mg/day, with 1/5 mg/day suggested to be an ineffective dose. Treatment with OFC has been associated with some side effects, including weight gain and the metabolic syndrome, somnolence, dry mouth, increased appetite and headache. Treatment decisions therefore need to be made to balance the risks and benefits.

Antidepressants and breast-feeding : a review of the literature

For every antidepressant so far investigated in the breast milk of mothers prescribed these medications, findings indicate that some amount of drug will be excreted into the breast milk. Nursing infants will be exposed to some, usually a very low, amount of drug and drugmetabolites. Levels of drug exposure to infants for the many antidepressants available are examined, discussing milk to plasma drug concentration ratios and the infant dose as a percentage of thematernal dose. Drug concentrations in infant plasma and adverse effects of drug exposures to infants are reviewed. Factors influencing the decision on whether to breast or bottle feed an infant nursed by a mother taking antidepressants are discussed, concluding that the decision needs to be made on an individual basis. The lactating mother, in consultation with her doctor, should be in a position to make an informed decision on whether or not to breast feed. Under certain circumstances the decision to bottle feed may be wise, but more commonly the advantages of breast-feeding will outweigh the very low risk of an adverse event from drug exposure to the infant.

Combination antidepressants : use by GPs and psychiatrists

Background : Current treatment of depression fails to achieve remission in 50% of patients. Combinations of two antidepressants are used by some Australian psychiatrists.

Objective : This article investigates the pros and cons of combination antidepressant therapy and provides suggestions for when to consider their use, which combinations to choose, and how to introduce combination antidepressant therapies.

Discussion : Combining two antidepressants is a controversial strategy, with supporters and critics arguing its efficacy and safety from opposing perspectives. The use of combination antidepressant therapies may facilitate remission from depression. However, there is limited evidence supporting these treatments, and safety concerns are often cited. There is some support for combination therapies in selected cases from international bodies. After considering risks and benefits on a case-by-case basis, careful use of selected combination antidepressant therapy may be one of a range of effective treatments for some individuals suffering from depression.

Combination pharmacotherapy in unipolar depression

It is estimated that between 60 and 80% of those with major depressive disorder do not achieve full symptomatic remission from first-line antidepressant monotherapy. Residual depressive symptoms substantially impair quality of life and add to the risk of recurrence. It is now clear that depression would benefit from more vigorous treatment, in order to ameliorate its disease burden. While there are established algorithms in situations of treatment resistance, the use of combination pharmacotherapy in unipolar depression is a relatively under-investigated area of treatment and may be an effective and tolerable strategy that maximizes the available resources. This paper reviews the current evidence for combination pharmacotherapy in unipolar depression and discusses its clinical applications.

A consensus statement for safety monitoring guidelines of treatments for major depressive disorder

Objective: This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring.
Method: Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content.
Results: Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment.
Conclusion: The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.

New drug targets in depression : inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

Maintenance N-acetyl cysteine treatment for bipolar disorder : a double-blind randomised placebo controlled trial

Background N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.

Method The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of [greater than or equal to]12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.

Results There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.

Conclusions There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. Trial Registration The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).