Vitamin D, SSRIs and the Musculoskeletal System
Condition: Major Depression; Osteoporosis
MeSH terms: Osteoporosis; Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

Summary: 
      In recent years it has become evident that some types of antidepressants are associated both
      with an increased risk of falling and decreased bone mineral density. These factors
      predispose patients for serious fractures such as hip fractures with substantial morbidity
      and mortality. The specific mechanisms involved in this negative impact on bone and postural
      control have not been fully elucidated. It is well known that Vitamin D plays an important
      role for bone health as well as muscle function and thus indirectly postural control.
      Furthermore, vitamin D deficiency has been observed among depressed patients. To our
      knowledge no study has investigated the involvement of Vitamin D in relation to the increased
      risk of fractures associated with antidepressants. Therefore, this project will investigate
      the underlying mechanisms leading to skeletal impairment and musculoskeletal symptoms in
      patients receiving different types of antidepressants. Moreover, the effect of vitamin D
      supplementation will be investigated among patients taking these antidepressants.

      150 subjects will participate in this study: 50 of which is diagnosed with depression and
      receive Citalopram (SSRIs); 50 depressed subjects receiving Mirtazapine(NaSRI); and 50
      controls. Through randomisation half of the subjects in each group will receive daily Vitamin
      D supplementation for a period of one year. Through this period all 150 subjects will be
      followed through different measurements including bone density, muscle function and balance,
      nociception, quality of life and depression severity.

      It is expected that results from this study will provide increasing awareness and knowledge
      of the side effect profile of antidepressants on bone metabolism. This may prompt clinicians
      to screen patients at high risk of drug-induced osteopenia or osteoporosis and accordingly
      provide treatment, which may reduce the incidence of potentially avoidable fractures.
      Moreover, some types of antidepressants may show to produce a minimal or even no effect on
      bone turnover, and should be considered as first line treatment in the group of patients at
      risk of fractures.
    

Detailed description: 
      Background

      Antidepressants are widespread in use, with more than 460.000 people in Denmark receiving
      this type of treatment ("Statens Serum Institut - Statistikker," 2012). Despite advances in
      medical treatment of depression in the last decades , recent studies have shown an
      association between the antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs) and
      increased risks of falls and decreased bone mineral density, resulting in increased risks of
      bone fractures. As SSRIs are prescribed as first line treatment for depression , such side
      effects could have detrimental effects for several patients.

      Residual symptoms such as tiredness, muscle weakness and muscle pain are observed in patients
      treated with antidepressants. It is not yet known if some of the residual symptoms of
      depression, and the negative effects on the skeleton may be mediated via decreased levels of
      vitamin D. Any decrease in vitamin D may be mediated either by the antidepressants or due to
      the depression per se (decreased exposure to sunlight and poor dietary habits). The treatment
      with antidepressants may improve the depression, but may not correct the vitamin D deficiency
      leaving residual symptoms, which may be interpreted as depression-related and this as
      incomplete response to the antidepressant treatment. Treatment with vitamin D may thus help
      alleviate some of the symptoms otherwise attributed to the depression leading to treatment
      with antidepressants (confounding by indication). Alternatively, antidepressants may
      interfere with biological processes that affect uptake or metabolism of Vitamin D resulting
      in low levels of the vitamin D that may have detrimental effects on bone turnover and muscle
      function.

      State-of-the-art For the antidepressants a difference has been observed between SSRI and the
      newer antidepressants. SSRI are associated with decreased bone mineral density and an
      increased risk of fractures, whereas for the newer antidepressants no increase in the risk of
      fractures has been seen , and little is known on their effect on bone density and bone
      turnover. This is concerning as they are in widespread use.

      The effects of SSRI may be mediated via direct serotoninergic effects on the bone cells and
      SSRIs and the newer antidepressants may affect the cardiovascular system, which may increase
      the risk of falls. The increased risk of falls may perhaps also be related to muscle weakness
      stemming from vitamin D deficiency or to effects on the central nervous system affecting
      postural balance. The risk of falls may explain an early increase in the risk of fractures,
      whereas any effects on bone density may increase long-term risk of fractures. In depressed
      patients reduced physical activity may also affect bone via disuse osteoporosis. It is thus
      not clear if some of the associations previously observed for antidepressants and detrimental
      skeletal effects may be mediated by the underlying disease (depression), or by factors
      related to the drugs themselves.

      Perspectives and relevance to the community If a cheap and simple treatment with vitamin D
      may improve quality of life and musculoskeletal status among depressed patients, this may
      e.g. bring many patients back to work and thus contribute significantly to public health.
      Moreover, information regarding the influence SSRIs has on bone turnover relative to postural
      control will contribute significantly to the unravelling of what mechanisms that are affected
      negatively by different SSRIs leading to increased risk of fractures. This will finally
      contribute to better understanding of the side effect profile of these drugs and hence enable
      better management of these in the clinic. This is of great value, since there, as stated
      earlier, is a large group of patients receiving this class of drug.

      Formulation of problem In recent years it has become evident that some types of
      antidepressants have a deleterious effect on bone metabolism with serious clinical
      consequences such as increased risk of fractures possibly with subsequent complications.
      Moreover, the majority of patients treated with antidepressants have residual symptoms
      including tiredness, muscle weakness and muscle pain, which are similar to symptoms of
      vitamin D deficiency. Increasing awareness and knowledge of the side effect profile of
      antidepressants on bone metabolism may prompt clinicians to screen patients at high risk of
      drug-induced osteopenia or osteoporosis and accordingly provide treatment, which may reduce
      the incidence of potentially avoidable fractures. Moreover, some types of antidepressants may
      show to produce a minimal or even no effect on bone turnover, and should be considered as
      first line treatment in the group of patients at risk of fractures. Therefore, this study,
      which consists of a cross-sectional and longitudinal study design, will address the following
      aims through biochemical and clinical characterisation: 1) to unravel underlying mechanisms
      leading to skeletal impairment and musculoskeletal symptoms or alterations in sensory-motor
      interactions (such as impaired balance) in patients receiving different types of
      antidepressants (selective serotonin reuptake inhibitors (SSRIs) or other newer
      antidepressants and 2) to investigate the effect of co-administrating vitamin D on bone
      status, sensory-motor interaction, and parameters associated with quality of life and
      depression in a randomised controlled clinical trial.

      Hypotheses:

        -  Decreased levels of Vitamin D may be caused by the depression by itself because of
           behavioural changes (less time outdoors and thus sun-exposure, and poor dietary habits)

        -  Certain types of antidepressants may alter the level of Vitamin D with a negative effect
           on the musculoskeletal system (residual symptoms) with measurable effects on postural
           control and bone mineral density (BMD).

        -  Decreased vitamin D levels may lead to musculoskeletal symptoms that are not corrected
           by treatment of the depression with antidepressants (Selective Serotonin Reuptake
           Inhibitors (SSRIs) or Noradrenergic and specific serotonergic Antidepressants (NaSSAs)).

        -  By supplementing with vitamin D some of the musculoskeletal symptoms and disruptions of
           bone status may be corrected.

        -  The increased risk of fractures is either caused by the SSRIs' effect on postural
           control and thus fall incidence or decreases in BMD, or a result of both.
    

Intervention name(s): cholecalciferol (50ug)
Intervention type(s): Dietary Supplement
Intervention description(s): The aim of the study was to investigate the effect of high dose vitamin D3 supplementation on the muscoloskeletal system among patients treated with antidepressants due to a diagnosis of major depressive disorder
Other intervention name(s): Vitamin D3 supplement
Intervention MeSH terms: Vitamin D; Cholecalciferol
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Two models are used, both a cross sectional study and a RCT. Corss sectional study: Patients (n=21) treated with citalopram (SSRI) due to major depressive disorder (MDD) are investigated for changes in bone mineral density, physcial performance (muscle strength, mobility, and balance), and pain sensitivity when compared to healthy controls (n=50).
RCT: Half of the patients and half of the controls are randomised (by double-blinding) to recieve either high dose vitamin D supplementation (2000 IU/day) of placebo for 12 months. All the primary endpoints from the cross sectional study will be assessed again after 6 and 12 months.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Vitamin D; Major depression; SSRIs; Osteoporosis