Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from in vitro and animal-based studies.

The regulation of bone metabolism continues to be an area of intense investigation, with recent evidence indicating a potential contribution from the neural system. In particular, the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has been hypothesized to play a role in skeletal metabolism via its transporter (5-HTT). The 5-HTT is a plasma membrane transporter that is highly specific for the uptake of extracellular 5-HT, thereby facilitating the intracellular storage and/or degradation of 5-HT. The 5-HTT is clinically important as it is the key target of pharmaceutical agents aimed at treating affective disorders, such as major depressive disorder. By antagonizing the 5-HTT, selective serotonin reuptake inhibitors (SSRIs) potentiate 5-HT activity and effectively relieve the symptoms of depression. However, questions have been raised regarding the potential skeletal effects of SSRIs given the recent identification of a functional 5-HTT and functional 5-HT receptors in bone cells. This paper discusses the preclinical evidence for the skeletal effects of 5-HT and the inhibition of the 5-HTT. In particular, it discusses the: (1) role of 5-HT and the function of the 5-HTT; (2) presence of functional 5-HTTs in bone; (3) potential sources and response mechanisms for 5-HT in bone, and; (4) in vitro and in vivo skeletal effects of 5-HT and 5-HTT inhibition.

Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies.

The discovery of a functional serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) in bone has given rise to questions about the physiologic role of 5-HT in bone, and the possible clinical implications for humans. 5-HT is known to play a role in the pathophysiology of depression, and many antidepressant medications function by inhibiting the 5-HTT. Among the antidepressants, those that selectively block the 5-HTT (namely, selective serotonin reuptake inhibitors; SSRIs) appear to have skeletal effects. Several studies have demonstrated lower bone density, increased rates of bone loss at the hip, and increased rates of fracture among older individuals taking SSRIs. However, there remains uncertainty about whether it is the antidepressant medications themselves or the reason for their use (depression) that is responsible for these observed bone changes. This paper reviews the epidemiologic literature that explores the role of the 5-HTT in bone health, by looking at questions about how depression, antidepressant therapy and SSRIs impact bone health in humans. Further research will be important to better understand how these factors interact to influence skeletal status, and to characterize the biochemical mechanism through which 5-HT may mediate bone turnover and metabolism.

Influence of menopause on mood: a systematic review of cohort studies.

OBJECTIVE: This systematic evidence review evaluates the independent influence of the menopausal transition on mood including depression, anxiety, and other psychological symptoms. METHODS: Community-based, prospective cohort studies of mid-life women transitioning through menopause that assessed at least one mood symptom on two or more occasions were identified by searches of MEDLINE (1966-2007) and PsycINFO (1974-2007) databases. Articles were selected based on predetermined inclusion and exclusion criteria. Each study was quality-rated by three authors; poor quality studies were excluded. RESULTS: Nine studies met inclusion criteria. They varied broadly in design, outcome measures, statistical methodology, and in consideration of and adjustment for important confounders. Five found no association between the menopausal transition and depression, negative mood, major depressive disorder, other psychological symptoms, and general mental health. Three found that women entering or completing the menopausal transition were more likely than premenopausal women to be depressed. One found that well-being increased from the early to late menopausal transition. CONCLUSION: There is no demonstrated pattern of an adverse independent influence of the menopausal transition on mood symptoms in mid-life women. However, the available studies are too methodologically diverse to be definitive.

Vitamin D insufficiency in internal medicine residents.

Medical residents may be vulnerable to low vitamin D status because of long work hours and lack of sun exposure. We conducted a prospective cohort study to measure serum 25-hydroxyvitamin D concentrations among internal medicine residents, document seasonal variation in vitamin D status, and assess risk factors for inadequate vitamin D stores. Dietary intake of calcium and vitamin D, lifestyle characteristics, and serum concentrations of 25(OH)-vitamin D and intact parathyroid hormone (iPTH) were measured in 35 resident volunteers before and after the winter season. A total of 63-69% of medical residents consumed <400 IU/day of vitamin D; 61-67% consumed <1000 mg/day of calcium. Twenty-five (74%) had lower serum 25(OH)-vitamin D concentrations and 23 (68%) had higher serum iPTH in the spring than in the fall. Nine (26%) residents had serum concentrations of 25(OH)-vitamin D of <20 ng/mL in the fall; and sixteen (47%) in the spring. Seven residents (20%) had serum concentrations of 25(OH)-vitamin D of <20 ng/mL at both time-periods; Eighteen residents (51.4%) had 25(OH)-vitamin D levels of <20 ng/mL for at least one of the time-periods. Medical residents are at risk for hypovitaminosis D, particularly during the winter months and should be aware of the need to supplement their vitamin D stores. Insufficient vitamin D status and inadequate vitamin D intake may have long-term implications for bone health in these individuals. Increased educational efforts to promote healthy dietary and lifestyle choices that allow attainment and maintenance of skeletal health are appropriate in this population.