Effects of antidepressants on postmenopausal bone loss - a 5-year longitudinal study from the OSTPRE cohort

BACKGROUND: Osteoporosis and depression are major health problems worldwide. The association between antidepressants, a treatment for depression, and bone health needs more detailed exploration. OBJECTIVE: The present study investigates antidepressant medication use and postmenopausal bone loss over time. METHODS: A total of 1988 women (aged 57-67) participating in the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) cohort responded to a postal enquiry and had their femoral neck bone mineral density (BMD) measured in 1999 and again in 2004. Data on antidepressant use was obtained from the National Prescription Register. Multiple regression techniques were used to test the associations, before and after adjustment for anthropometric, medical, physical and lifestyle factors. RESULTS: Over the five years of follow-up, 319 (16.0%) women purchased antidepressants. Mean baseline femoral neck BMD for the entire study group was 881mg/cm(2) (SD 123) and mean 5-year bone loss was 6.0mg/cm(2) (SD 4.7). After adjustments, users of tricyclic antidepressants (TCA) had greater annual BMD loss than non-users (-3.6mg/cm(2) vs. -1.1mg/cm(2); P=0.031). Accelerated bone loss was also associated with selective serotonin reuptake inhibitor's (SSRI) use (P=0.001) and use of other antidepressants in a dose-response way, with the latter only among women of low-weight and normal-weight women who had lost weight over the study period. CONCLUSIONS: In conclusion, the use of SSRIs seems to accelerate postmenopausal bone loss in a dose-response manner. Associations between TCA and other antidepressant use and bone loss may also exist. Thus, the possibility of increased risk of osteoporosis should be considered when prescribing antidepressants for postmenopausal women.

Cost-effectiveness of cognitive-behavioural therapy and drug interventions for major depression

Objective: Antidepressant drugs and cognitive–behavioural therapy (CBT) are effective treatment options for depression and are recommended by clinical practice guidelines. As part of the Assessing Cost-effectiveness – Mental Health project we evaluate the available evidence on costs and benefits of CBT and drugs in the episodic and maintenance treatment of major depression.

Method: The cost-effectiveness is modelled from a health-care perspective as the cost per disability-adjusted life year. Interventions are targeted at people with major depression who currently seek care but receive non-evidence based treatment. Uncertainty in model inputs is tested using Monte Carlo simulation methods.

Results: All interventions for major depression examined have a favourable incremental cost-effectiveness ratio under Australian health service conditions. Bibliotherapy, group CBT, individual CBT by a psychologist on a public salary and tricyclic antidepressants (TCAs) are very cost-effective treatment options falling below $A10 000 per disability-adjusted life year (DALY) even when taking the upper limit of the uncertainty interval into account. Maintenance treatment with selective serotonin re-uptake inhibitors (SSRIs) is the most expensive option (ranging from $A17 000 to $A20 000 per DALY) but still well below $A50 000, which is considered the affordable threshold.

Conclusions: A range of cost-effective interventions for episodes of major depression exists and is currently underutilized. Maintenance treatment strategies are required to significantly reduce the burden of depression, but the cost of long-term drug treatment for the large number of depressed people is high if SSRIs are the drug of choice. Key policy issues with regard to expanded provision of CBT concern the availability of suitably trained providers and the funding mechanisms for therapy in primary care.

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.

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.

Schizophrenia, psychotropic medication, and cataract

OBJECTIVE: To compare the distribution of cataract types between psychiatric patients diagnosed with schizophrenia and the general population not exposed to psychotropic medication, and to compare cataract prevalence between users and nonusers of various psychotropic medications in the general community. DESIGN: Case-control. PARTICIPANTS: A total of 151 (93%) eligible patients from a community mental health service and 3271 (83%) eligible residents from the Melbourne Visual Impairment Project (VIP) were examined. MAIN OUTCOME MEASURES: All patients 40 years of age and older from a community mental health service and residents of nine randomly selected areas of Melbourne were eligible. Best-corrected distance visual acuity was determined using a 4-m logarithm of the minimum angle of resolution (LogMAR) chart. The presence of cataract was determined by photographs or slit-lamp examination using direct and indirect retroillumination. Anterior, cortical, nuclear, and posterior subcapsular cataracts were measured. Participants from the Melbourne VIP were classified as to whether they had taken benzodiazepams, phenothiazines, thioxanthenes, butyrophenols, tricyclic antidepressants, or monoamine oxidase inhibitors for at least 12 months during their lifetime. RESULTS: The distribution of cataract type varied between persons with and without schizophrenia. Anterior subcapsular (ASC) cataract was significantly more prevalent (26%) in participants with schizophrenia from the community mental health service than Melbourne VIP participants (0.2%) not exposed to psychotropic medication (chi-square, 1 degree of freedom = 605.5, P = 0.001). This remained significant after controlling for age (odds ratios = 250, 95% confidence interval = 83.3, 1000). The distribution of the age-related cataract was similar across all groups of psychotropic medication users with the exception of the phenothiazine users. They had less of all types of the age-related cataracts, despite being slightly older than the control group (mean age, 60.0 vs. 58.4, t test = 0.85, P = 0.40). However, only cortical cataract in the phenothiazine group was statistically lower (chi-square, 1 degree of freedom = 3.96, P = 0.047). CONCLUSION: This study has identified the need to investigate whether other newer agents, especially high-potency medications, cause ASC opacities if a certain threshold of exposure to psychotropic medications must be attained to develop cataract, or if schizophrenia itself is associated with cataract formation.

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.

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.

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.

A survey of combination antidepressant use in Australia

Objective: The aim of this study was to survey doctors working in psychiatry in Australia about the practice of using two antidepressants simultaneously.

Method: A postal survey was sent to all doctors in psychiatry in Australia enquiring about their prescribing history and their attitudes to combination antidepressants and related issues.

Results: Seventy-nine percent of respondents had used combination antidepressants. The most frequently reported combination was a selective serotonin reuptake inhibitor combined with a tricyclic antidepressant. Combinations of mirtazepine with venlafaxine and other antidepressants were the next most frequently used. Seventeen percent of respondents reported having seen a complication from combination antidepressants, 75% believed that Australian GPs should be given information on the use of combination antidepressants, 89% wished for more information on this topic, and 88% believed patients had a right to be informed of this option in their treatment. Use of combination antidepressants was more frequent than exceeding the recommended maximum dose of an individual antidepressant.

Conclusion: Combination antidepressants are used far more frequently in Australia than suspected previously. Research into safe and evidence-based practice is strongly indicated.

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.