Kegg Pathway: Antidepressants

J Sep Sci. 2008 Jul 21; 31(13): 2358-2370
Uddin MN, Samanidou VF, Papadoyannis IN

A novel method for the simultaneous determination of six benzodiazepines (BZDs) and four tricyclic Antidepressants (TCAs) in biological fluids by HPLC with UV detection at 240 nm has been developed. After a deproteinization step biological fluids were analyzed by direct injection. SPE on Nexus cartridges was also applied. Since two compounds, namely imipramine and diazepam, were coeluting, a sequential SPE protocol has been developed. BZDs were eluted by a mixture of methanol/ACN (1:1), followed by the elution of TCAs with methanol. Separation was performed on a Kromasil C(8 )column (250x4 mm(2) id, 5 mum) using a mobile phase of 0.05 M CH(3)COONH(4)/ACN/methanol (initial composition 55:15:30 v/v/v) at a flow rate of 1.0 mL/min delivered by a gradient program within 15 min. Colchicine was used as the internal standard (4 ng/muL). The method was linear for all analytes up to 20 ng/muL, with coefficients of regression between 0.996 and 0.99996. LODs and LOQs were 0.08-1.17 and 0.28-3.91 ng/muL, respectively. Recovery was in the range of 92.8-108.7% for within-day and 91.9-109.9% for between-day assays, with RSD values lower than 10.0% for all matrices.

J Clin Psychiatry. 2008 Jul 15; e1-e6
Volpe FM

BACKGROUND: Although major depression and chronic headache are strongly associated, there is insufficient evidence for the use of Antidepressants for this specific comorbidity. This trial aimed to investigate the efficacy and tolerability of duloxetine for this indication. METHOD: Thirty outpatients with DSM-IV major depressive disorder and concurrent primary chronic headache (chronic migraine, chronic tension-type headache, or both), 18 to 55 years old, were recruited from April 2006 to March 2007, if they scored > 21 on the Montgomery-Asberg Depression Rating Scale (MADRS) and had no other significant clinical condition. Subjects received duloxetine 60 mg/day for 8 weeks. Scores on the MADRS and a visual analog pain scale (VAS) were the co-primary outcome measures. Scores on the brief version of the World Health Organization Quality of Life scale (WHOQoL-BREF) and number of headache days/week were secondary outcome measures. The study was conducted at the Liaison-Psychiatry Service of SOCOR General Hospital, Belo Horizonte, Brazil. RESULTS: Mean +/- SD MADRS scores decreased significantly from baseline to endpoint (29.5 +/- 5.2 to 8.9 +/- 8.7 points, p < .001), and mean +/- SD VAS scores decreased significantly from 5.8 +/- 1.9 to 1.9 +/- 2.5 points (p < .001). Combined intent-to-treat response rate (> 50% reduction on MADRS and > 40% on VAS) was 66.7% (20/30). Significant improvements in both headache and depression were evident after the first week. Mean +/- SD WHOQoL-BREF scores increased (improved) 18.8 +/- 21.9 points (p < .001), and mean +/- SD number of headache days/week decreased from 5.2 +/- 2.0 to 2.9 +/- 2.5 days/week (p < .001). Two subjects discontinued for side effects and 3 for nonadherence. CONCLUSION: In this preliminary open trial, duloxetine 60 mg/day was effective, fast acting, and well tolerated for the treatment of comorbid major depressive disorder and chronic headache. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00531895.

Neuropharmacology. 2008 Jun 29;
Hwang J, Zheng LT, Ock J, Lee MG, Kim SH, Lee HW, Lee WH, Park HC, Suk K

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may contribute to neuronal cell death. Inhibition of glial activation may alleviate neurodegeneration under these conditions. In the present study, the antiinflammatory and neuroprotective effects of tricyclic Antidepressants were investigated using cultured brain cells as a model. The results showed that clomipramine and imipramine significantly decreased the production of nitric oxide or tumor necrosis factor-alpha (TNF-alpha) in microglia and astrocyte cultures. Clomipramine and imipramine also attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and TNF-alpha at mRNA levels. In addition, clomipramine and imipramine inhibited IkappaB degradation, nuclear translocation of the p65 subunit of NF-kappaB, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated microglia cells. Moreover, clomipramine and imipramine were neuroprotective as the drugs reduced microglia-mediated neuroblastoma cell death in a microglia/neuron co-culture. Therefore, these results imply that clomipramine and imipramine have antiinflammatory and neuroprotective effects in the central nervous system by modulating glial activation.

Rheum Dis Clin North Am. 2008 May; 34(2): 433-53
Perrot S, Javier RM, Marty M, Le Jeunne C, Laroche F

This article reviews the pharmacologic and clinical evidence supporting the use of antidepressant drugs for treating painful rheumatologic conditions. Clinical studies have shown that tricyclic Antidepressants, even at low doses, have analgesic effects in rheumatologic conditions equivalent to those of serotonin and noradrenalin reuptake inhibitors, but are less well tolerated. Selective serotonin reuptake inhibitors may also have analgesic effects, but higher doses are required to achieve analgesia in conditions such as fibromyalgia and low back pain. Antidepressant drugs may be useful in painful rheumatologic conditions, but in some studies the analgesic effects of Antidepressants may be associated with functional impairment, sleep disorders, and fatigue. Further studies are required to determine Antidepressants' analgesic mechanism of action and the specific role they should play in the management of chronic painful rheumatologic conditions.

BMC Complement Altern Med. 2008 Jul 17; 8(1): 42
Clauson KA, Santamarina ML, Rutledge JC

ABSTRACT: BACKGROUND: St. John's wort (SJW), used to treat depression, is popular in the USA, Canada, and parts of Europe. However, there are documented interactions between SJW and prescription medications including warfarin, cyclosporine, indinavir, and oral contraceptives. One source of information about these safety considerations is the product label. The aim of this study was to evaluate the clinically relevant safety information included on labeling in a nationally representative sample of SJW products from the USA. METHODS: Eight clinically relevant safety issues were identified: drug interactions (SJW-HIV medications, SJW-immunosupressants, SJW-oral contraceptives, and SJW-warfarin), contraindications (bipolar disorder), therapeutic duplication (Antidepressants), and general considerations (phototoxicity and advice to consult a healthcare professional (HCP)). A list of SJW products was identified to assess their labels. Percentages and totals were used to present findings. RESULTS: Of the seventy-four products evaluated, no product label provided information for all 8 evaluation criteria. Three products (4.1%) provided information on 7 of the 8 criteria. Four products provided no safety information whatsoever. Percentage of products with label information was: SJW-HIV (8.1%), SJW-immunosupressants (5.4%), SJW-OCPs (8.1%), SJW-warfarin (5.4%), bipolar (1.4%), Antidepressants (23.0%), phototoxicity (51.4%), and consult HCP (87.8%). Other safety-related information on labels included warnings about pregnancy (74.3%), lactation (64.9%), discontinue if adverse reaction (23.0%), and not for use in patients under 18 years old (13.5%). The average number of a priori safety issues included on a product label was 1.91 (range 0-8) for 23.9% completeness. CONCLUSION: The vast majority of SJW products fail to adequately address clinically relevant safety issues on their labeling. A few products do provide an acceptable amount of information on clinically relevant safety issues which could enhance the quality of counseling by HCPs and health store clerks. HCPs and consumers may benefit if the FDA re-examined labeling requirements for dietary supplements.

Int J Oncol. 2008 Aug; 33(2): 277-86
Gil-Ad I, Zolokov A, Lomnitski L, Taler M, Bar M, Luria D, Ram E, Weizman A

Evidence has been provided of the anti-proliferative activity of certain Antidepressants, mainly the selective serotonin reuptake inhibitors (SSRIs). We tested the effect of different Antidepressants on cell viability and proliferation of human colorectal carcinoma cell lines HT29 and the multi-drug resistant (MDR) LS1034. The SSRIs, paroxetine and sertraline, induced a dose-dependent inhibition of cell viability and proliferation in the two cell lines (IC50 8-15 microM). When compared to cytotoxic agents e.g. doxorubicin, vincristine and 5-fluorouracil, the SSRIs showed comparable activity (HT29) or a superior effect (LS1034). Using flow cytometry analysis, we found that the two SSRIs arrested cells at the G0/G1 stage and stimulated DNA fragmentation in a dose-dependent manner. The SSRIs (10 and 20 microM) increased caspase-3 activation. Western blot analysis showed an increase after 24 h in c-Jun and a decrease in the expression of the anti-apoptotic protein Bcl-2. The results suggest a proapoptotic activity for the active SSRIs accompanied by mitogen-activated protein kinase cascade activation and Bcl-2 inhibition. In vivo, we used CD1 nude mice xenografted subcutaneously with HT29 cells. On day 8, after cell inoculation sertraline or paroxetine (15 mg/kg x3/week i.p.) were administered to animals (6/group), which were monitored weekly (for 5 weeks) for tumor volume and body weight. At 5 weeks, the animals survived, with no significant difference in body weight. Sertraline, though not paroxetine, significantly inhibited tumor growth. Collectively, our results suggest that the widely-used antidepressant, sertraline, possesses a potential anti-tumor activity, which circumvents the MDR mechanism. Since SSRI therapy is frequently indicated in cancer patients, the use of sertraline in colon cancer patients with co-morbidity of depression seems attractive.

J Psychopharmacol. 2008 Jun; 22(4): 452-6
Franks M, Macritchie K, Mahmood T, Young A

In bipolar disorder the discontinuation of lithium prophylaxis is associated with early episode precipitation. Is this ;rebound' phenomenon peculiar to lithium? This naturalistic retrospective case note review investigated the frequency of immediate recurrence after discontinuation of any prophylactic treatment. Bipolar patients who stopped at least one medication after at least 6 months of remission were studied. A total of 310 case notes were examined in a systematic search. A total of 53 cases of discontinuation in 48 subjects were found. Discontinued medications included lithium, valproate, carbamazepine, typical and atypical antipsychotics and Antidepressants. Recurrence occurred within 3 months of medication withdrawal in 39 cases (74%). Over half of the discontinuation episodes involved lithium: recurrence occurred in 86% of these cases. In the groups stopping other prophylactic agents, a majority of subjects suffered recurrence: anticonvulsants (89%), antipsychotics (64%) and Antidepressants (58%). However, these groups were small and the clarity of the data was undermined by the simultaneous withdrawal of other agents. Manic and hypomanic episodes were the most common form of recurrences. Depressive episodes occurred proportionately most frequently following antidepressant withdrawal. More than half of recurrences required hospital admission. This study provides preliminary naturalistic evidence that early episode recurrence in bipolar disorder is not peculiar to lithium withdrawal but may occur following withdrawal of medication from all classes recommended in prophylaxis. These findings, if replicated, have important implications for clinical practice and for research.

Neuropharmacology. 2008 Jun 27;
Harmer CJ

There is growing interest in the effects of antidepressant drug treatment on measures of emotional processing. Such actions may help us understand the role of monoamines in emotional dysfunction in depression and how antidepressant drug treatments work. Recent studies suggest that decreasing central serotonin function with tryptophan depletion can reinstate negative biases in recovered depressed patients, even at doses insufficient to induce changes in mood. Conversely, antidepressant drug administration increases the processing of positive emotional information in healthy volunteers and acutely depressed patients early in treatment. This increase in positive bias may provide a platform for subsequent cognitive restructuring and learning which contributes to the evolution of symptom change in depression. Functional neuroimaging studies suggest that these early antidepressant effects involve fronto-limbic and extra-striate circuitry suggestive of actions on both the initial appraisal and attentional processing of affective stimuli. This approach may therefore provide a framework for linking psychological and biological processes in emotional disorders and their treatment. Antidepressants may not directly modulate mood and anxiety but rather allow a different perspective for our ongoing evaluation of our self, the world and the future.

Health Econ Policy Law. 2007 Jan; 2(Pt 1): 23-49
Cuellar AE, Markowitz S

In recent years, Medicaid has experienced a dramatic increase in spending on prescription drugs in general and psychotropic medications in particular. The purpose of this study is to examine the effects of increased Medicaid spending on psychotropic drugs on improving the mental health and well-being of participants at the population level. Specifically, we study the effect on outcomes that are strongly correlated with mood disorders, including depression and Attention Deficit/Hyperactivity disorder, controlling for concomitant increases in Medicaid eligibility thresholds and expansion into managed care for mental health services. Knowledge of the effects of changes in the Medicaid program is crucial to policymakers as they consider implementing and expanding mental health services. Our results show that increased spending on Antidepressants and stimulants are associated with improvements in some outcomes, but not in others.

J Nucl Med. 2008 Jul 16;
Arakawa R, Okumura M, Ito H, Seki C, Takahashi H, Takano H, Nakao R, Suzuki K, Okubo Y, Halldin C, Suhara T

(S,S)-(18)F-FMeNER-D2 was recently developed as a radioligand for the measurement of norepinephrine transporter imaging with PET. In this study, a norepinephrine transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. METHODS: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-(18)F-FMeNER-D2. Binding potential relative to nondisplaceable binding (BPND) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120-180 min. The caudate was used as reference brain region. RESULTS: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BPND values by the indirect kinetic method were 0.54 +/- 0.19 and 0.35 +/- 0.25 in the thalamus and locus coeruleus, respectively. BPND values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r = 0.81-0.92). CONCLUSION: The regional distribution of (S,S)-(18)F-FMeNER-D2 in our study agreed with that demonstrated by previous PET and postmortem studies of norepinephrine transporter in the human brain. The ratio method with a time integration interval of 120-180 min will be useful for clinical research of psychiatric disorders for estimation of norepinephrine transporter occupancy by Antidepressants without requiring arterial blood sampling and dynamic PET.

Support Cancer Ther. 2007 Sep 1; 4(4): 219-24
Barton DL, Loprinzi CL, Atherton P, Raymond J, Shanafelt T, Hines S, Palmieri F, Rummans T, Adjei AA, Sloan J

Purpose: Newer Antidepressants with serotonergic effects reduce hot flashes significantly better than placebo. This pilot study was designed to test the efficacy of desipramine, an older antidepressant targeting norepinephrine, in women desiring therapy for hot flashes and to evaluate the toxicity of desipramine. Patients and Methods: In this nonrandomized trial, eligible women were required to have reported >/= 14 bothersome hot flashes per week for >/= 1 month. After an Initials baseline week in which no study medication was taken, participants started with desipramine 25 mg daily, which was titrated to100 mg daily by week 5. The primary endpoint was change from baseline in hot flash frequency and hot flash score. Statistical methods involved paired t tests for continuous variables and Fisher exact tests for categoric variables. Results: Twenty-six patients were enrolled on this study between March 2004 and November 2005. The decrease in mean hot flash frequency over 4 weeks of treatment was 23%, with a 31% reduction in hot flash scores. Seven patients (30%) withdrew early because of toxicities consisting of insomnia, nausea, headaches, and/or feeling frightened. Conclusion: Desipramine did not reduce hot flashes beyond the 25%-30% reduction that would be expected with placebo, based on previous work. Therefore, data from this trial do not support further study of this agent for treatment of hot flashes. It is of physiologic interest that this older antidepressant, classified as a tricyclic, did not achieve a clinically significant reduction in hot flash scores in this pilot trial.

Crit Care Med. 2008 Jul; 36(7 Suppl): S346-57
Malchow RJ, Black IH

BACKGROUND: The evolution of military medical care to manage polytrauma, critically ill-wounded warriors from the greater war on terrorism has been accompanied by significant changes in the diagnosis, management, and modulation of acute and chronic trauma-related pain. A paradigm shift in pain management includes early treatment of pain at the point of injury and throughout the continuum of care with a combination of standard and novel therapeutic interventions. These concepts are important for all critical care providers because they translate to most critically ill patients, including those resulting from natural disasters. Previous authors have reported a high incidence of moderate to severe pain and poor analgesia in intensive care units associated with sleep disturbances, tachycardia, pulmonary complications, increased stress response with thromboembolic incidents, and immunosuppression, increased intensive care unit and hospital stays, and needless suffering. Although opioids have traditionally been the cornerstone of acute pain management, they have potential negative effects ranging from sedation, confusion, respiratory depression, nausea, ileus, constipation, tolerance, opioid-induced hyperalgesia as well as potential for immunosuppression. Alternatively, multimodal therapy is increasingly recognized as a critical pain management approach, especially when combined with early nutrition and ambulation, designed to improve functional recovery and decrease chronic pain conditions. DISCUSSION: Multimodal therapy encompasses a wide range of procedures and medications, including regional analgesia with continuous epidural or peripheral nerve block infusions, judicious opioids, acetaminophen, anti-inflammatory agents, anticonvulsants, ketamine, clonidine, mexiletine, Antidepressants, and anxiolytics as options to treat or modulate pain at various sites of action. SUMMARY: With a more aggressive acute pain management strategy, the military has decreased acute and chronic pain conditions, which may have application in the civilian sector as well.

Psychopharmacology (Berl). 2008 Jul 16;
Sillaber I, Panhuysen M, Henniger MS, Ohl F, Kühne C, Pütz B, Pohl T, Deussing JM, Paez-Pereda M, Holsboer F

INTRODUCTION: Monoamine-based Antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve-indicating the involvement of effects distant from reuptake inhibition. OBJECTIVE: To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression. MATERIALS AND METHODS: The behavioral response to long-term paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology. RESULTS AND DISCUSSION: Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice. CONCLUSION: Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.

Cancer Epidemiol Biomarkers Prev. 2008 Jul; 17(7): 1564-95
Moysich KB, Beehler GP, Zirpoli G, Choi JY, Baker JA

Prescription and over-the-counter medications are widely used in the United States and many western countries. More than two-thirds of women ages >45 years, who are at greatest risk for breast cancer, take prescription medication. In light of the ubiquitous nature of medication use and the fact that breast cancer remains the most common cancer in women, research on the role of medication use in breast cancer etiology is warranted. We summarize the epidemiologic evidence on the association between breast cancer risk and use of common medications, including antibiotics, Antidepressants, statins, antihypertensives, and nonsteroidal anti-inflammatory drugs. Overall, there is little evidence that would implicate the use of antibiotics, Antidepressants, statins, and antihypertensives in the etiology of breast cancer. Although several prospective studies and a randomized low-dose aspirin chemoprevention trial have not shown lower risk of breast cancer among aspirin users, most studies that have examined the potential chemoprotective effect of nonsteroidal anti-inflammatory drugs have shown significant risk reductions for regular and prolonged use of these drugs. The existing literature on the role of medication use in breast carcinogenesis is complicated. Interpretation of the evidence is hampered due to major methodologic differences across studies, including exposure assessment, exposure classification, and adjustment for potential confounding variables. These differences largely stem from the fact that the majority of articles on this topic represent secondary data analyses from studies with inadequate information on exposure or confounders. Thus, future epidemiologic studies specifically designed to study these ubiquitous and biologically plausible exposures are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1564-95).

Med J Aust. 2008 Jun 16; 188(12 Suppl): S119-25
Gunn JM, Gilchrist GP, Chondros P, Ramp M, Hegarty KL, Blashki GA, Pond DC, Kyrios M, Herrman HE

OBJECTIVES: To report the baseline characteristics of the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) study cohort and discuss the implications for depression care in general practice. DESIGN: A prospective longitudinal study beginning in January 2005. PARTICIPANTS AND SETTING: Adult patients with depressive symptoms identified via screening with the Center for Epidemiologic Studies Depression Scale (CES-D > or = 16) in 30 randomly selected Victorian general practices. MAIN OUTCOME MEASURE: Depression status on the Patient Health Questionnaire (PHQ). RESULTS: 789 patients form the cohort (71% women). At baseline, 47% were married, 21% lived alone, 36% received a pension or benefit, 15% were unable to work, 23% reported hazardous drinking, 32% were smokers, 39% used Antidepressants and 19% used sedatives. 27% satisfied criteria for current major depressive syndrome (MDS) on the PHQ, while 52% had "persistent" depressive symptoms, and 22% had "transient" depressive symptoms, lasting at most a few weeks. Of those satisfying criteria for MDS, 49% were also classified with an anxiety syndrome, 40% reported childhood sexual abuse, 57% reported childhood physical abuse, 42% had at some time been afraid of their partner, and 72% reported a chronic physical condition; 84% were receiving mental health care (either taking Antidepressants or seeing a health practitioner specifically for mental health care) compared with 66% of those with persistent depressive symptoms and 57% with transient depressive symptoms. CONCLUSION: This method of screening for depressive symptoms in general practice identifies a group of patients with substantial multiple comorbidities -- psychiatric, physical and social problems coexist with depressive symptoms, raising challenges for the management of depression in general practice.

J Clin Psychopharmacol. 2008 Aug; 28(4): 468-70
Katz MM

J Clin Psychopharmacol. 2008 Aug; 28(4): 467-8
Deshauer D, Moher D, Fergusson D

J Clin Psychopharmacol. 2008 Aug; 28(4): 447-51
Rickels K, Garcia-Espana F, Mandos LA, Case GW

Anxiety disorders are the most common mental illnesses in the United States. Despite having a number of medication options readily available, benzodiazepines (BZs) and Antidepressants have achieved remission rates of only 35% after 8 weeks of acute treatment. In the development of new anxiolytics, particularly those that affect the gamma-aminobutyric acid system, it is essential to assess the new compound's potential to cause discontinuation symptoms after stopping the medication as part of both short- and long-term treatment. This report describes the development of the 20-item Penn Physician Withdrawal Checklist (PWC), a smaller version of the original 35-item PWC, and examines its validity, internal consistency, test-retest and interrater reliability, and factor structure. The PWC scores, assessed at the peak of withdrawal severity, were selected from 143 of our patients for an orthogonal factor analysis. Our results suggest that the Penn Physician Withdrawal Checklist is a simple and accurate method to assess anxiolytic discontinuation symptoms.

J Clin Psychopharmacol. 2008 Aug; 28(4): 411-7
Ziere G, Dieleman JP, van der Cammen TJ, Hofman A, Pols HA, Stricker BH

BACKGROUND: Fractures related to osteoporosis and falling constitute a major health problem in the elderly population. Exposure to Antidepressants is associated with an increased risk of falls and fractures, but most previous studies incriminate tricyclic Antidepressants (TCAs) rather than selective serotonin reuptake inhibitors (SSRIs). OBJECTIVE: To examine the association between Antidepressants, including TCAs, SSRIs, and other Antidepressants and the risk of nonvertebral fractures in elderly. DESIGN: Prospective population-based cohort study. SETTING: The Rotterdam Study, consisting of 7983 individuals aged 55 years and older. PARTICIPANTS: All persons from the Rotterdam Study. RESULTS: One thousand two hundred nineteen persons experienced a nonvertebral fracture, 25 during TCA use and 18 during SSRI use. After adjustment for age, sex, lower-limb disability, and depression, the risk of nonvertebral fracture was 2.35 (95% confidence interval, 1.32-4.18) for current users of SSRIs compared with nonusers of Antidepressants. Multiple adjusting for many possible risk factors did not affect the association. To deal with potential confounding by indication, we subsequently restricted the analysis to antidepressant users (n = 1217). Compared with past users of TCAs or SSRIs, current users of SSRIs had a 2.07-fold (95% confidence interval, 1.23-3.50) increased risk of fracture, which further increased with prolonged use. In this analysis, depressive state at baseline and during follow-up did not play a role, suggesting absence of confounding by indication. The use of TCAs was associated with an increased fracture risk that decreased with prolonged use. CONCLUSIONS: Not only users of TCAs but also of SSRIs have a significantly increased risk of nonvertebral fractures, in SSRI users especially after prolonged use. Despite fewer early adverse effects of SSRIs, physicians treating elderly depressive patients should be aware of the unfavorable long-term consequence of SSRIs on fracture risk.

J Clin Psychopharmacol. 2008 Aug; 28(4): 384-91
Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, and antipsychotics have each been associated with an increased risk of fracture in older individuals. The aim of this study was to better define the magnitude of fracture risk with psychotropic medications and to determine whether a dose-effect relationship exists. METHODS: Population-based administrative databases were used to examine psychotropic medication exposure and fractures in persons aged 50 years and older in Manitoba between 1996 and 2004. Persons with osteoporotic fractures (vertebral, wrist, or hip [n = 15,792]) were compared with controls (3 controls for each case matched for age, sex, ethnicity, and comorbidity [n = 47,289]). Medications examined included Antidepressants (SSRIs vs other monoamines), antipsychotics, lithium, and benzodiazepines. RESULTS: Selective serotonin reuptake inhibitors were associated with the highest adjusted odds of osteoporotic fractures (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.32-1.59). Other monoamine Antidepressants (OR = 1.15; 95% CI, 1.07-1.24) and benzodiazepines (OR = 1.10; 95% CI, 1.04-1.16) were also associated with greater fracture risk, although the relationship was weaker. Lithium was associated with lower fracture risk (OR = 0.63; 95% CI, 0.43-0.93), whereas the relationship with antipsychotics was not significant in the models that adjusted for diagnoses. A dose-effect relationship was seen with SSRIs and benzodiazepines. CONCLUSIONS: This study provides novel insight into the relationship between fractures and psychotropic medications in the elderly. Selective serotonin reuptake inhibitors seem to have a greater risk than other psychotropic classes, and higher doses may further increase that risk. Lithium seems to be protective against fractures.