Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

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Major depressive disorder

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)00234-2.pdf

Suicide and suicidal behaviour

Background:The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines r...

https://journals.sagepub.com/doi/pdf/10.1177/0706743716659417

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder Section 3. Pharmacological Treatments

Objectives To investigate the association between antidepressant treatment and risk of several potential adverse outcomes in older people with depression and to examine risks by class of antidepressant, duration of use, and dose. Design Cohort study of people aged 65 and over diagnosed as having depression. Setting 570 general practices in the United Kingdom supplying data to the QResearch primary care database. Participants 60 746 patients diagnosed as having a new episode of depression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 and followed up until 31 December 2008. Main outcome measures Hazard ratios associated with antidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction, stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potential confounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use and for commonly prescribed individual drugs. Results 54 038 (89.0%) patients received at least one prescription for an antidepressant during follow-up. A total of 1 398 359 antidepressant prescriptions were issued: 764 659 (54.7%) for selective serotonin reuptake inhibitors, 442 192 (31.6%) for tricyclic antidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189 305 (13.5%) for the group of other antidepressants. The associations with the adverse outcomes differed significantly between the antidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated with the highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) and hyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. The group of other antidepressants was associated with the highest adjusted hazard ratios for all cause mortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transient ischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to 3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes. Significantly different associations also existed between the individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, and venlafaxine (both in the group of other antidepressants) were associated with the highest rates for some of these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while not taking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotonin reuptake inhibitors, and 11.43% for other antidepressants. Conclusions Selective serotonin reuptake inhibitors and drugs in the group of other antidepressants were associated with an increased risk of several adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone, mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is an observational study, it is susceptible to confounding by indication, channelling bias, and residual confounding, so differences in characteristics between patients prescribed different antidepressant drugs that could account for some of the associations between the drugs and the adverse outcomes may remain. Further research is needed to confirm these findings, but the risks and benefits of different antidepressants should be carefully evaluated when these drugs are prescribed to older people.

https://www.bmj.com/content/bmj/343/bmj.d4551.full.pdf

Antidepressant use and risk of adverse outcomes in older people: Population based cohort study

Objectives: To provide guidance for the management of mood disorders, based on scientific evidence supplemented by expert clinical consensus and formulate recommendations to maximise clinical salience and utility. Methods: Articles and information sourced from search engines including PubMed and EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (MDC) (e.g., books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Information was reviewed and discussed by members of the MDC and findings were then formulated into consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous successive consultation and external review involving: expert and clinical advisors, the public, key stakeholders, professional bodies and specialist groups with interest in mood disorders. Results: The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (Mood Disorders CPG) provide up-to-date guidance and advice regarding the management of mood disorders that is informed by evidence and clinical experience. The Mood Disorders CPG is intended for clinical use by psychiatrists, psychologists, physicians and others with an interest in mental health care.

/pdf/royal-australian-and-new-zealand-college-of-psychiatrists-29brj3xyri.pdf

Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders

Objective To examine the risk of suicidal behaviour within clinical trials of antidepressants in adults. Design Meta-analysis of 372 double blind randomised placebo controlled trials. Setting Drug development programmes for any indication in adults. Participants 99 231 adults assigned to antidepressants or placebo. Median age was 42 and 63.1% were women. Indications for treatment were major depression (45.6%), other depression (4.6%), other psychiatric disorders (27.6%), and non-psychiatric disorders (22.2%). Main outcome measures Suicidal behaviour (completed suicide, attempted suicide, or preparatory acts) and ideation. Results For participants with non-psychiatric indications, suicidal behaviour and ideation were extremely rare. For those with psychiatric indications, risk was associated with age. For suicidal behaviour or ideation and for suicidal behaviour only, the respective odds ratios were 1.62 (95% confidence interval 0.97 to 2.71) and 2.30 (1.04 to 5.09) for participants aged Conclusions Risk of suicidality associated with use of antidepressants is strongly age dependent. Compared with placebo, the increased risk for suicidality and suicidal behaviour among adults under 25 approaches that seen in children and adolescents. The net effect seems to be neutral on suicidal behaviour but possibly protective for suicidal ideation in adults aged 25-64 and to reduce the risk of both suicidality and suicidal behaviour in those aged ≥65.

https://www.bmj.com/content/bmj/339/bmj.b2880.full.pdf

Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration

Therecently published observational study by Zivin et al. (1) examined the risk of cardiac arrhythmias andmortality among patients taking high-dosage (.40mg/day), medium-dosage (21–40 mg/day), and low-dosage (#20 mg/day) citalopram. The authors concluded that high-dosage citalopram was not associated with increased rates of cardiac arrhythmias or overall mortality compared with lowdosage citalopram. Indeed, higher dosages were associated with fewer adverse outcomes; the unadjusted mortality rate for patients taking high dosages was about half that observed with low dosages. On the basis of their findings, they questioned the FDA’s warning to avoid dosages exceeding 40 mg/day. The approach the authors took, however, was unlikely to detect differences in potentially life-threatening arrhythmias, and for reasons explained below, we believe the 60 mg/day citalopram dosage should be avoided. A randomized, placeboand activecontrolled,double-blind,dose-escalation, crossover study (a “thoroughQTstudy”) has unequivocally demonstrated dosedependent QT prolongation with citalopram. The 60 mg/day dosage caused greater prolongation (18.5 ms) than lower dosages (20 mg/day, 8.5 ms; 40 mg/day, 12.6 ms) and the standard active control drug known to prolong the QT interval (moxifloxacin, 13.4 ms) (2). Although the magnitude of QT effect leading to concern is a matter of judgment, QT prolongation above 15 ms can increase the risk of potentially fatal torsade de pointes-type ventricular tachycardia (3). Under real-world conditions, drug interactions can magnify the effect, as has been demonstrated with citalopram and pimozide (4). Most important, even if the increase in mortality risk from the 60 mg/day dosage is small, use of that dosage cannot be justified, as it was not more effective than 40 mg/day in phase 3 trials (5). Therefore, the FDA updated the labeling for citalopram and, in 2011 and 2012, issued drug safety communications advising avoidance of citalopram dosages above 40 mg/day (2). Observational studies using large administrative databases have not been successful for identifying drug-induced torsade de pointes (6). None of eight observational cohort studies conducted to evaluate the cardiac safety of cisapride or terfenadine, which have been removed from the U.S. market because they clearly cause torsade de pointes, showed an increased risk with either drug (6–8). Torsade de pointes is rare, even with drugs that unequivocally cause it; the incidence rate is estimated to be in the range of 1 per 12,000 to 120,000 patients (6). Moreover, a person who develops fatal ventricular tachycardia or ventricular fibrillation

Cardiac safety concerns remain for citalopram at dosages above 40 mg/day.

Antiepileptic drugs and suicide attempts in patients with bipolar disorder.

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2 ). The current study used that model to assess the impact on respiration of non-benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone-paroxetine co-administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug-drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co-administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.

Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat.

Sharma and colleagues essentially duplicate, with more limited data, many of the analyses presented in our 2009 paper but seem not to have read our paper very carefully.1 2 They write, “The FDA did not consider the limitations of the trials that we identified and introduced some of their own—for example, by …

Marc Stone

Papers

Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration

Cardiac safety concerns remain for citalopram at dosages above 40 mg/day.

Antiepileptic drugs and suicide attempts in patients with bipolar disorder.

Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat.

Suicidality and aggression during antidepressant treatment: authors misinterpreted earlier paper from the FDA