Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents

Objective:
To assess from a health sector perspective the incremental cost-effectiveness of cognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) for the treatment of major depressive disorder (MDD) in children and adolescents, compared to ‘current practice’.
Method:
The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analysis of randomised controlled trials. An assessment on second stage filter criteria (‘equity’; ‘strength of evidence’, ‘feasibility’ and ‘acceptability to stakeholders’) is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are tracked for the duration of a new episode of MDD arising in eligible children (age 6–17 years) in the Australian population in the year 2000. Simulation-modelling techniques are used to present a 95% uncertainty interval (UI) around the cost-effectiveness ratios.
Results:
Compared to current practice, CBT by public psychologists is the most costeffective intervention for MDD in children and adolescents at A$9000 per DALY saved (95% UI A$3900 to A$24 000). SSRIs and CBT by other providers are less cost-effective but likely to be less than A$50 000 per DALY saved (> 80% chance). CBT is more effective than SSRIs in children and adolescents, resulting in a greater total health benefit (DALYs saved) than could be achieved with SSRIs. Issues that require attention for the CBT intervention include equity concerns, ensuring an adequate workforce, funding arrangements and acceptability to various stakeholders.
Conclusions:
Cognitive behavioural therapy provided by a public psychologist is the most
effective and cost-effective option for the first-line treatment of MDD in children and adolescents. However, this option is not currently accessible by all patients and will require change in policy to allow more widespread uptake. It will also require ‘start-up’ costs and attention to ensuring an adequate workforce.

Selective serotonin reuptake inhibitors in mixed anxiety-depression.

The overlap between the depressive and anxiety disorders is extremely common. The introduction of the selective serotonin reuptake inhibitors (SSRIs) has, more than any other development, bridged the gap in terms of efficacy in both sets of disorders. A substantial body of data exists suggesting that the available SSRIs have substantial efficacy in anxiety symptoms co-occurring with depression. The clear utility of the SSRIs in disorders classified apart from depression is also established. Whilst panic disorder is the best studied, evidence on the efficacy of the SSRIs in disorders that previously did not attract much pharmacotherapeutic interest, such as social anxiety disorder and post-traumatic stress disorder is accumulating.

Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. OBJECTIVE: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. METHODS: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc >440 msec. RESULTS: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5-21.3) and 30 of 469 (6.4%; 95% CI 4.3-9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p=0.0002); citalopram (450 IQR: 436-484) was individually different to fluoxetine (p=0.045), fluvoxamine (p=0.022), paroxetine (p=0.0002), and sertraline (p=0.001). The proportion of citalopram overdoses with a QTc >440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32-11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p=0.026); citalopram (400 IQR: 380-440) was individually different from sertraline (p=0.023). CONCLUSIONS: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease.

Cost-effectiveness of psychological and pharmacological interventions for generalized anxiety disorder and panic disorder

Objective: To assess from a health sector perspective the incremental cost-effectiveness of interventions for generalized anxiety disorder (cognitive behavioural therapy [CBT] and serotonin and noradrenaline reuptake inhibitors [SNRIs]) and panic disorder (CBT, selective serotonin reuptake inhibitors [SSRIs] and tricyclic antidepressants [TCAs]).

Method: The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analyses of randomised controlled trials. An assessment on second stage filters ('equity', 'strength of evidence', 'feasibility' and 'acceptability to stakeholders') is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are calculated for a period of one year for the eligible population (prevalent cases of generalized anxiety disorder/panic disorder identified in the National Survey of Mental Health and Wellbeing, extrapolated to the Australian population in the year 2000 for those aged 18 years and older). Simulation modelling techniques are used to present 95% uncertainty intervals (UI) around the incremental cost-effectiveness ratios (ICERs).

Results: Compared to current practice, CBT by a psychologist on a public salary is the most cost-effective intervention for both generalized anxiety disorder (A$6900/DALY saved; 95% UI A$4000 to A$12 000) and panic disorder (A$6800/DALY saved; 95% UI A$2900 to A$15 000). Cognitive behavioural therapy results in a greater total health benefit than the drug interventions for both anxiety disorders, although equity and feasibility concerns for CBT interventions are also greater.

Conclusions: Cognitive behavioural therapy is the most effective and cost-effective intervention for generalized anxiety disorder and panic disorder. However, its implementation would require policy change to enable more widespread access to a sufficient number of trained therapists for the treatment of anxiety disorders.

Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.
Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.
Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).
In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Anxiety disorders : assessment and management in general practice

Background: Anxiety is a normal physiological response to a threat. Anxiety disorders occur when this normal physiological response is associated with high levels of autonomic arousal, erroneous cognitions and dysfunctional coping strategies. Anxiety disorders are highly prevalent and present commonly to general practice. Anxiety disorders are often comorbid with other psychiatric and medical disorders and may be associated with significant morbidity.

Objective: This article describes the diagnosis, assessment and management of anxiety disorders in the general practice setting.

Discussion: Assessment in patients presenting with anxiety symptoms involves excluding a medical cause, identifying features of specific anxiety disorders as well as other coexisting psychiatric disorders, and assessing the degree of distress. Management options include psychoeducation, psychological treatments (particularly cognitive behaviour therapy) and pharmacological treatments. Patients with a diagnosis of an anxiety disorder can access Medicare funded psychological care under a number of Australian government initiatives. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are the first line pharmacological agents used to treat anxiety disorders. Regular review is vital to monitor for clinical improvement and more complex presentations may require specialist psychological or psychiatric referral.

The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): study protocol for a randomised control trial.

The aim of the Youth Depression Alleviation-Combined Treatment (YoDA-C) study is to determine whether antidepressant medication should be started as a first-line treatment for youth depression delivered concurrently with psychotherapy. Doubts about the use of medication have been raised by meta-analyses in which the efficacy and safety of antidepressants in young people have been questioned, and subsequent treatment guidelines for youth depression have provided only qualified support.

The association between use of antidepressants and bone quality using quantitative heel ultrasound.

Osteoporosis and depression are major public health problems worldwide. Studies have reported an association between antidepressant use, mainly selective serotonin reuptake inhibitors (SSRIs), and bone mineral density (BMD), but the issue remains unclear.

Is implementation of the 2013 Australian treatment guidelines for posttraumatic stress disorder cost-effective compared to current practice? A cost-utility analysis using QALYs and DALYs

To assess, from a health sector perspective, the incremental cost-effectiveness of three treatment recommendations in the most recent Australian Clinical Practice Guidelines for posttraumatic stress disorder (PTSD). The interventions assessed are trauma-focused cognitive behavioural therapy (TF-CBT) and selective serotonin reuptake inhibitors (SSRIs) for the treatment of PTSD in adults and TF-CBT in children, compared to current practice in Australia.

Citalopram and sertraline exposure compromises embryonic bone development

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.Molecular Psychiatry advance online publication, 8 September 2015; doi:10.1038/mp.2015.135.

Effects of depression and serotonergic antidepressants on bone: mechanisms and implications for the treatment of depression

Osteoporosis is a chronic skeletal disease marked by microarchitectural deterioration of the bone matrix and depletion of bone mineral density (BMD), with a consequent increased risk for fragility fractures. It has been frequently associated with depression, which is also a chronic and debilitating disorder with high prevalence. Selective serotonin reuptake inhibitors (SSRIs), first-line agents in the pharmacological treatment of mood and anxiety disorders, have also been shown to negatively affect bone metabolism. SSRIs are the most prescribed antidepressants worldwide and a large number of persons at risk of developing osteoporosis, including older patients, will receive these antidepressants. Therefore, a proper musculoskeletal evaluation of individuals who are being targeted for or using SSRIs is a priority. The aim of this article is to review the evidence regarding the effects of depression and serotonergic antidepressants on bone and its implications for clinical care.