Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

Cost-effectiveness of genetic and clinical predictors for choosing combined psychotherapy and pharmacotherapy in major depression.

BACKGROUND: Predictors of treatment outcome in major depressive disorder (MDD) could contribute to evidence-based therapeutic choices. Combined pharmacotherapy and psychotherapy show increased efficacy but higher cost compared with antidepressant pharmacotherapy; baseline predictors of pharmacotherapy resistance could be used to identify patients more likely to benefit from combined treatment. METHODS: We performed a proof-of-principle study of the cost-effectiveness of using previously identified pharmacogenetic and clinical risk factors (PGx-CL-R) of antidepressant resistance or clinical risk factors alone (CL-R) to guide the prescription of combined pharmacotherapy and psychotherapy vs pharmacotherapy. The cost-effectiveness of these two strategies was compared with standard care (ST, pharmacotherapy to all subjects) using a three-year Markov model. Model parameters were literature-based estimates of response to pharmacotherapy and combined treatment, costs (UK National Health System) and benefits (quality-adjusted life years [QALYs], one QALY=one year lived in perfect health). RESULTS: CL-R was more cost-effective than PGx-CL-R: the cost of one-QALY improvement was £2341 for CL-R and £3937 for PGx-CL-R compared to ST. PGx-CL-R had similar or better cost-effectiveness compared to CL-R when 1) the cost of genotyping was £100 per subject or less or 2) the PGx-CL-R test had sensitivity ≥ 0.90 and specificity ≥ 0.85. The cost of one-QALY improvement for CL-R was £3664 and of £4110 in two independent samples. LIMITATIONS: lack of validation in large samples from the general population. CONCLUSIONS: Using clinical risk factors to predict pharmacotherapy resistance and guide the prescription of pharmacotherapy combined with psychotherapy could be a cost-effective strategy.

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Reconfiguration of functional brain networks and metabolic cost converge during task performance.

The ability to solve cognitive tasks depends upon adaptive changes in the organization of whole-brain functional networks. However, the link between task-induced network reconfigurations and their underlying energy demands is poorly understood. We address this by multimodal network analyses integrating functional and molecular neuroimaging acquired concurrently during a complex cognitive task. Task engagement elicited a marked increase in the association between glucose consumption and functional brain network reorganization. This convergence between metabolic and neural processes was specific to feedforward connections linking the visual and dorsal attention networks, in accordance with task requirements of visuo-spatial reasoning. Further increases in cognitive load above initial task engagement did not affect the relationship between metabolism and network reorganization but only modulated existing interactions. Our findings show how the upregulation of key computational mechanisms to support cognitive performance unveils the complex, interdependent changes in neural metabolism and neuro-vascular responses.

Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography.

Background: Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans. Methods: Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. Results: After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Conclusions: Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses.

Assessment and management of agitation in psychiatry: Expert consensus.

BACKGROUND: Psychomotor agitation is associated with different psychiatric conditions and represents an important issue in psychiatry. Current recommendations on agitation in psychiatry are not univocal. Actually, an improper assessment and management may result in unnecessary coercive or sedative treatments. A thorough and balanced review plus an expert consensus can guide assessment and treatment decisions. METHODS: An expert task force iteratively developed consensus using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new, re-worded or re-rated items. RESULTS: Out of 2175 papers assessing psychomotor agitation, 124 were included in the review. Each component was assigned a level of evidence. Integrating the evidence and the experience of the task force members, a consensus was reached on 22 statements on this topic. CONCLUSIONS: Recommendations on the assessment of agitation emphasise the importance of identifying any possible medical cause. For its management, experts agreed in considering verbal de-escalation and environmental modification techniques as first choice, considering physical restraint as a last resort strategy. Regarding pharmacological treatment, the "ideal" medication should calm without over-sedate. Generally, oral or inhaled formulations should be preferred over i.m. routes in mildly agitated patients. Intravenous treatments should be avoided.

Individual diversity of functional brain network economy.

On average, brain network economy represents a trade-off between communication efficiency, robustness, and connection cost, although an analogous understanding on an individual level is largely missing. Evaluating resting-state networks of 42 healthy participants with seven Tesla functional magnetic resonance imaging and graph theory revealed that not even half of all possible connections were common across subjects. The strongest similarities among individuals were observed for interhemispheric and/or short-range connections, which may relate to the essential feature of the human brain to develop specialized systems within each hemisphere. Despite this marked variability in individual network architecture, all subjects exhibited equal small-world properties. Furthermore, interdependency between four major network economy metrics was observed across healthy individuals. The characteristic path length was associated with the clustering coefficient (peak correlation r=0.93), the response to network attacks (r=-0.97), and the physical connection cost in three-dimensional space (r=-0.62). On the other hand, clustering was negatively related to attack response (r=-0.75) and connection cost (r=-0.59). Finally, increased connection cost was associated with better response to attacks (r=0.65). This indicates that functional brain networks with high global information transfer also exhibit strong network resilience. However, it seems that these advantages come at the cost of decreased local communication efficiency and increased physical connection cost. Except for wiring length, the results were replicated on a subsample at three Tesla (n=20). These findings highlight the finely tuned interrelationships between different parameters of brain network economy. Moreover, the understanding of the individual diversity of functional brain network economy may provide further insights in the vulnerability to mental and neurological disorders.

Compliance as a stable function in the treatment course of bipolar disorder in patients stabilized on olanzapine: results from a 24-month observational study.

Compliance is a key factor in the maintenance treatment of bipolar disorder. This noninterventional study was conducted to explore factors associated with higher levels of compliance in bipolar patients, all treated in routine clinical settings. Bipolar outpatients (Clinical Global Impression of Severity score ≤3) who had been stabilized with olanzapine mono- or combination therapy for ≥4 weeks were enrolled in the study. Compliance to medication was assessed at baseline and after 3, 6, 9, 12, 18, and 24 months by a physician-rated, 4-point categorical scale using the following classification: noncompliant (patients being compliant to treatment schedule less than 20% of the time) and low (20% to 59% of the time), moderate (60% to 79% of the time), and high (≥80% of the time) levels of compliance. Both baseline and post-baseline factors were used in a generalized estimating equations (GEE) model to predict the likelihood of high compliance. Of 891 eligible patients, 657 patients completed the 24-month observation period. High levels of compliance (≥80%) were observed in 67% of patients at baseline, increasing to 80% in study completers. High compliance at baseline was identified as a strong predictor of compliance during study participation (odds ratio (OR) = 6.9, 95% confidence interval (CI) = 5.0 to 9.5, p < 0.001). Factors associated with high compliance during the study (GEE model) included greater life satisfaction (p = 0.002), better insight into illness (p < 0.001), less work impairment (p = 0.007), and fewer days of inpatient care (p = 0.002). Compliance ratings varied by country (p < 0.001) and duration of post-baseline treatment (p = 0.014). In conclusion, a number of clinical, functional, and social factors were identified as predictors of compliance in patients with bipolar disorder. As compliance is crucial for the long-term management of these patients, more attention should be directed towards compliance itself and factors associated with compliance levels in everyday treatment settings.

A gap analysis for future supply of and demand for psychiatrists in Austria.

BACKGROUND: In the recent past, a rising caseload demonstrates increasing demand for psychiatrists, and ageing of the current mental health workforce will soon result in growing numbers of retirees. Under these conditions there is some concern whether we soon will face widening gaps in supply. AIMS OF THE STUDY: This study calculates projections of future use and supply of psychiatrists' services in Austria until 2030. Resulting gaps are calculated for different scenarios. DATA AND METHODS: We mostly use administrative data from several public authorities. To estimate the demand for services, we start from utilization data rather than medical need for services, as we do not have sufficient epidemiological information for Austria. We define several scenarios for the future development of use, all calculated separately for hospital and non-hospital services. Future supply of psychiatric services is projected by applying activity levels to projected numbers of physicians, which are calculated using a stock and flow model. Outflows are modeled using assumptions derived from past activity patterns and current legislation on retirement. To model inflows, we need to gauge the impact of recent developments: Entrance barriers into medical education were introduced, Austria experienced a surge of medical students coming from Germany, and medical schools implemented quotas for different nationalities. Scenarios take several factors into account, like the shifting sex composition of the medical workforce, re-migration of foreign students, and the impact of entrance barriers on enrolment and drop-out rates. RESULTS: Depending on scenario assumptions, demand for psychiatrists will increase by 8% to 52%. But in all supply scenarios, supply will decline from 2016 onwards, thus widening gaps between supply and demand. Even in the most optimistic scenario, supply will have fallen below current levels by 2030. DISCUSSION: Compared to current rates of service use, a gap between supply and demand will start to widen soon. In the most optimistic combination of scenarios, demand will exceed supply from 2028 onwards, and the projected gap will amount to about 5% of projected demand for services in 2030. LIMITATIONS: Gaps could be miscalculated due to lack of more detailed data, such as retirement patterns of psychiatrists. Shifting responsibilities between psychiatrists and other (mental) health workers as well as changes in psychiatrists' "productivity", e.g. due to more effective medications, were not modeled but would affect results. IMPLICATIONS FOR HEALTH POLICIES: It will be necessary to improve working and training conditions in order to avoid emigration and to attract a sufficient number of young entrants into the profession.

Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder.

Discontinuation effects following cessation of 12 and 24 wk of pregabalin treatment for generalized anxiety disorder (GAD) were evaluated in a placebo- and lorazepam-controlled, randomized, double-blind, multicentre trial conducted in 16 countries. The study design consisted of two 12-wk treatment periods (periods 1 and 2), each followed by a 1-wk taper and two post-discontinuation assessments, one immediately following the taper and one 1-wk post-taper. Patients were assigned to receive an initially flexible dose of pregabalin 450-600 mg/d, pregabalin 150-300 mg/d, or lorazepam 3-4 mg/d for 6 wk; responders continued fixed-dose therapy for 6 additional weeks. Patients entering period 2 continued on the same fixed dose or switched to placebo. Discontinuation effects were evaluated with the Physician Withdrawal Checklist (PWC) and reported discontinuation-emergent signs and symptoms. Rebound anxiety was measured with the Hamilton Anxiety Rating Scale. GAD symptoms improved with all treatments and improvements were maintained over 12 and 24 wk. Low levels of discontinuation symptoms were evident in all treatment groups. For patients who received active treatment during both periods, mean (95% confidence interval) increases on the PWC from last visit on active treatment to the second post-discontinuation assessment were: pregabalin 450-600 mg/d: 2.8 (1.6-3.9), pregabalin 150-300 mg/d: 1.7 (0.7-2.8), lorazepam 3-4 mg/d: 2.2 (1.0-3.5). Rates of rebound anxiety were also low at both 12 and 24 wk (0-6%). This suggests that risk of discontinuation symptoms and rebound anxiety are low for pregabalin after 12 and 24 wk of treatment.

The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder.

OBJECTIVES: These guidelines are based on a first edition that was published in 2004, and have been edited and updated with the available scientific evidence up to October 2012. Their purpose is to supply a systematic overview of all scientific evidence pertaining to the long-term treatment of bipolar disorder in adults. METHODS: Material used for these guidelines are based on a systematic literature search using various data bases. Their scientific rigor was categorised into six levels of evidence (A-F) and different grades of recommendation to ensure practicability were assigned. RESULTS: Maintenance trial designs are complex and changed fundamentally over time; thus, it is not possible to give an overall recommendation for long-term treatment. Different scenarios have to be examined separately: Prevention of mania, depression, or an episode of any polarity, both in acute responders and in patients treated de novo. Treatment might differ in Bipolar II patients or Rapid cyclers, as well as in special subpopulations. We identified several medications preventive against new manic episodes, whereas the current state of research into the prevention of new depressive episodes is less satisfactory. Lithium continues to be the substance with the broadest base of evidence across treatment scenarios. CONCLUSIONS: Although major advances have been made since the first edition of this guideline in 2004, there are still areas of uncertainty, especially the prevention of depressive episodes and optimal long-term treatment of Bipolar II patients.

Do we need another atypical antipsychotic?

Atypical antipsychotics were a great advance in the treatment of schizophrenia. But, there is still no atypical antipsychotic with an exceptional efficacy and safety profile for all patients. Clinicians are required to draw on their experiential knowledge to examine suitable options for individual patients. Following its suspension in 1998, the safety and efficacy of sertindole have been investigated in several post-marketing studies based in clinical settings. These have provided the safety data to support the reintroduction of sertindole, as well as specific examples demonstrating that certain patients, in particular, may benefit from a switch from other atypical antipsychotics to sertindole. Sertindole's individual and mostly favourable profile of treatment-emergent effects and safety allows for flexibility in treating patients. The propensity of sertindole to cause anticholinergic effects, which can be particularly troublesome, is small and, more recently, there have been suggestions that sertindole may have beneficial effects on cognition.

A review of the evidence for carbamazepine and oxcarbazepine in the treatment of bipolar disorder.

Bipolar disorder is a recurrent lifelong condition associated with significant morbidity and mortality. The main goals of treatment are the acute management of manic/depressive episodes and the prevention of recurrence. Mood stabilizers are the basis of most treatment regimens. Although lithium is the classical mood stabilizer, dissatisfaction with its efficacy and tolerability has led to increased use of other mood- stabilizing agents, including anticonvulsants. Newer anticonvulsants such as oxcarbazepine may offer improved tolerability and fewer drug-drug interactions compared to older drugs like carbamazepine. A search of the literature shows that data from controlled clinical studies support the efficacy of carbamazepine in treating acute mania and as maintenance therapy. In addition, a growing body of data for oxcarbazepine suggests that this newer agent may have a similar efficacy profile to carbamazepine, with improved tolerability. This review presents a balanced selection of the key studies on carbamazepine and oxcarbazepine in bipolar disorder.

Cost-effectiveness analysis of escitalopram: a new SSRI in the first-line treatment of major depressive disorder in Austria.

OBJECTIVES: To compare the cost-effectiveness of escitalopram, a new selective serotonin reuptake inhibitor (SSRI), with (generic) citalopram in the first-line treatment of major depressive disorder (MDD) in Austria. METHODS: A two-path decision analytic model with a 6-month horizon was adapted to the Austrian setting using Austrian clinical guidelines. All patients (aged >or= 18 years) started at the primary successfully treated patient was lower ( currency 115) for care path and were referred to specialist care in the secondary care path in case of insufficient response. Model inputs included drug-specific probabilities from head-to-head trial data, literature and expert opinion. The main outcome measure was success (i.e., remission defined as Montgomery-Asberg Depression Rating Scale (MADRS) score

Cost-effectiveness of escitalopram versus citalopram in the treatment of severe depression.

BACKGROUND: Severe depression is associated with an extensive economic burden on both the patient and society. OBJECTIVE: To estimate the cost-effectiveness in Austria of escitalopram compared with citalopram in the management of severe depression (Montgomery-Asberg Depression Rating Scale score > or =30). METHODS: A decision model incorporated treatment paths and associated direct resource use (psychiatric hospitalization, medications, general practitioner and psychiatrist visits, treatment discontinuation, suicide attempts) associated with managing severe depression and the indirect cost of work absenteeism over a 6-month period. Main outcomes were clinical success (remission at 6 mo) and cost (2002 Euros equals approximately 1.25 US) of treatment. The analysis was performed from the Austrian societal and Social Healthcare Insurance System (SHIS) perspectives. Clinical input data were derived from a meta-analysis of 8-week randomized clinical trials. Costs were derived from standard Austrian price lists or from the literature. RESULTS: Six months after the start of treatment, the overall clinical success remission rate was higher for escitalopram (53.7%) than for citalopram (48.7%). From the SHIS perspective, the total expected cost per successfully treated severely depressed patient was 924 (32.1%) lower for escitalopram (2879) compared with citalopram (3803). From the societal perspective, the total expected cost per successfully treated severely depressed patient was 1369 (24.4%) lower for escitalopram (5610) than for citalopram (6979). Sensitivity analyses demonstrated that the model was robust and that, even if citalopram had no acquisition cost, escitalopram remained the dominant strategy for both perspectives. CONCLUSIONS: Treatment with escitalopram was the dominant strategy. These data suggest that escitalopram is a cost-effective antidepressant compared with citalopram in the management of severe depression in Austria.