Platelet glutamate receptor supersensitivity in major depressive disorder.

Dysregulation of glutamate has been described in depression, and supersensitivity of platelet glutamate receptors has been found in both psychotic major depression and schizophrenia. The aim of this study was to examine the platelet glutamate receptor sensitivity in patients with nonpsychotic, unipolar major depression to assess whether this is a marker of depression or of psychosis. Glutamate receptor sensitivity was assessed using the platelet intracellular calcium response to glutamate (0-100 micromol) measured by spectrofluorometry. The depression group showed a significantly greater platelet intracellular calcium response to glutamate stimulation than the control group, both in terms of absolute values (p = 0.007) and percentage of response from baseline (p = 0.030). These data suggest that platelet glutamate receptors may be supersensitive in depression and that the platelet may be a possible peripheral marker of glutamate function in depression.

Platelet supersensitivity to thrombin stimulation in depression: a possible mechanism for the association with cardiovascular mortality.

The mortality risk associated with cardiovascular disease is significantly increased in patients with major depression and panic disorder. The mechanism of this phenomenon is unclear. Thrombin is responsible for platelet aggregation and shape change, and it plays a significant role in the development of thromboembolic events. In this study, we examined the platelet second messenger intracellular calcium response to thrombin stimulation in patients with major depression (n = 13), major depression after response to electroconvulsive therapy (ECT; n = 13), subsyndromal depression (n = 16), schizophrenia (n = 15), and control subjects (n = 65). Patients with major depression had significantly higher intracellular calcium responses to thrombin stimulation than control subjects, patients with subsyndromal depression, and patients with schizophrenia (p < 0.05). Electroconvulsive therapy did not significantly change this supersensitivity. This suggests that the platelet response to activation in patients with major depression is supersensitive. This study suggests a possible mechanism for the increased risk of cardiovascular disease that is seen in these two psychiatric disorders. The lack of difference between the control and subsyndromal depression groups appears to validate current diagnostic thresholds in depression. The failure of nonpharmacologic treatment to alter this marker suggests that it may be a trait marker of depression.

Supersensitive platelet glutamate receptors as a possible peripheral marker in schizophrenia.

Hypoglutamatergic function is implicated in the pathogenesis of schizophrenia. The aim of this study was to examine the platelet intracellular calcium response to glutamate using spectroflourometry in 15 schizophrenic patients and 15 matched control individuals as an index of platelet glutamate receptor sensitivity. Patients with schizophrenia had significantly lower baseline intracellular calcium levels than matched control individuals (P = 0.03). The percentage response of the schizophrenic individuals to glutamate stimulation was significantly greater than control individuals (P < 0.001). These data suggest that platelet glutamate receptors may be supersensitive in schizophrenia. Furthermore, the platelet may be a possible peripheral marker of glutamate function in schizophrenia.

Citalopram-associated clitoral priapism: a case series.

Priapism is documented to occur in association with treatment with a variety of psychotropic agents. Three cases of clitoral priapism associated with treatment with citalopram are presented.

The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men.

OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.

Effects of persisting emotional impact from child abuse and norepinephrine transporter genetic variation on antidepressant efficacy in major depression: a pilot study

OBJECTIVE: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and antidepressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. METHODS: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. RESULTS: No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. CONCLUSIONS: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.

Associations of obsessive-compulsive symptoms with clinical and neurocognitive features in schizophrenia according to stage of illness

This study aimed to investigate the association of obsessive-compulsive symptoms with clinical and neurocognitive features in patients with schizophrenia. This study enrolled 163 people with schizophrenia who were receiving risperidone monotherapy. Comorbid obsessive-compulsive symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale, and subjects with a score ≥ 10 constituted the obsessive-compulsive symptom group (n=30, 18.4%). The learning index was significantly higher in patients with obsessive-compulsive symptoms than in those without such symptoms after adjusting for age, stage (early and chronic), duration of illness, and CDSS score. However, there was no significant interaction between obsessive-compulsive symptoms and stage of illness. Scores on Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Beck Depression Inventory were significantly higher in the obsessive-compulsive symptom group. In addition, the Subjective Well-being under Neuroleptic Treatment score was significantly lower in the obsessive-compulsive symptom group. In conclusion, comorbid obsessive-compulsive symptoms in patients with schizophrenia were associated with a higher learning ability without a significant interaction with stage of illness. However, schizophrenia patients with obsessive-compulsive symptoms had more severe psychotic and depressive symptoms and poorer quality of life.

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.

Variation at the DRD4 locus is associated with wariness and local site selection in urban black swans

 BACKGROUND: Interactions between wildlife and humans are increasing. Urban animals are often less wary of humans than their non-urban counterparts, which could be explained by habituation, adaptation or local site selection. Under local site selection, individuals that are less tolerant of humans are less likely to settle in urban areas. However, there is little evidence for such temperament-based site selection, and even less is known about its underlying genetic basis. We tested whether site selection in urban and non-urban habitats by black swans (Cygnus atratus) was associated with polymorphisms in two genes linked to fear in animals, the dopamine receptor D4 (DRD4) and serotonin transporter (SERT) genes.

RESULTS: Wariness in swans was highly repeatable between disturbance events (repeatability = 0.61) and non-urban swans initiated escape from humans earlier than urban swans. We found no inter-individual variation in the SERT gene, but identified five DRD4 genotypes and an association between DRD4 genotype and wariness. Individuals possessing the most common DRD4 genotype were less wary than individuals possessing rarer genotypes. As predicted by the local site selection hypothesis, genotypes associated with wary behaviour were over three times more frequent at the non-urban site. This resulted in moderate population differentiation at DRD4 (FST = 0.080), despite the sites being separated by only 30 km, a short distance for this highly-mobile species. Low population differentiation at neutrally-selected microsatellite loci and the likely occasional migration of swans between the populations reduces the likelihood of local site adaptations.

CONCLUSION: Our results suggest that wariness in swans is partly genetically-determined and that wary swans settle in less-disturbed areas. More generally, our findings suggest that site-specific management strategies may be necessary that consider the temperament of local animals.

Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT) mice and mice with deficient tryptophan hydroxylase 2 (TPH2) function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI) mice. Whereas, maternal separation (MS) stress increased anxiety-and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2, KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A). The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex), will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7-11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7-11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7-11, Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety-and depressive-like behaviors.

Chemical modulators of lipid abundance and bone development

 My research focussed on the analysing the lipid profile during development. I further studied potential chemicals to modulate lipid abundaces. Furthermore, I explored the effects of SSRIs on bone development.

Depression as a risk factor for fracture in women: a 10 year longitudinal study

BACKGROUND: Previous research has demonstrated deficits in bone mineral density (BMD) among individuals with depression. While reduced BMD is a known risk for fracture, a direct link between depression and fracture risk is yet to be confirmed. METHODS: A population-based sample of women participating in the Geelong Osteoporosis Study was studied using both nested case-control and retrospective cohort study designs. A lifetime history of depression was identified using a semi-structured clinical interview (SCID-I/NP). Incident fractures were identified from radiological reports and BMD was measured at the femoral neck using dual energy absorptiometry. Anthropometry was measured and information on medication use and lifestyle factors was obtained via questionnaire. RESULTS: Among 179 cases with incident fracture and 914 controls, depression was associated with increased odds of fracture (adjusted odds ratio (OR) 1.57, 95%CI 1.04-2.38); further adjustment for psychotropic medication use appeared to attenuate this association (adjusted OR 1.52, 95%CI 0.98-2.36). Among 165 women with a history of depression at baseline and 693 who had no history of depression, depression was associated with a 68% increased risk of incident fracture (adjusted hazard ratio (HR) 1.68, 95%CI 1.02-2.76), with further adjustment for psychotropic medication use also appearing to attenuate this association (adjusted HR 1.58, 95%CI 0.95-2.61). LIMITATIONS: Potential limitations include recall bias, unrecognised confounding and generalizability. CONCLUSIONS: This study provides both cross-sectional and longitudinal evidence to suggest that clinical depression is a risk factor for radiologically-confirmed incident fracture, independent of a number of known risk factors. If there is indeed a clinically meaningful co-morbidity between mental and bone health, potentially worsened by psychotropic medications, the issue of screening at-risk populations needs to become a priority.

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.