Vitamin D, SSRIs and the Musculoskeletal System
Vitamin D, SSRIs and the Musculoskeletal System
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.
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.
Inclusion Criteria:

 -  Current Citalopram or Mirtazapine users < 6 months, or individuals who are going to
 initiate treatment of either Citalopram, Mirtazapine within the following two months
 or

 -  Healthy controls, i.e. not depressed or receiving antidepressants

 Exclusion Criteria:

 -  Current or use within the past 6 months of drugs which affects bone turnover such as
 corticosteroids, hormone replacement therapy in postmenopausal women, drugs against
 osteoporosis or other bone diseases (Paget's disease of bone), vitamin D
 supplementation (>35 micrograms daily), Depot Medroxyprogesterone Acetate (DMPA),
 Cyclosporine (CsA), Antiretroviral Therapy (ART)

 -  Impaired renal function (serum creatinine > 150 micromolar/l)

 -  Pregnant women

 -  Individuals diagnosed with cancer or a metabolic disorder such as diabetes

 -  Individuals with prosthetic material in hip or spine

 -  Individuals diagnosed with a disease that affects bone such as Paget's disease of the
 bone, or fibrous dysplasia

 -  Individuals which is not considered eligible for the clinical trial e.g. individuals
 diagnosed with dementia, severely psychotic or depressed individuals

 -  Individuals that have been taking any kind of antidepressants more than 6 months prior
 to the inclusion and if this treatment persisted for a period of minimum 12 months

 -  Individuals which cannot stand up and stand still without support or a helping device
 due to physically impairment