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June 2007

An NSAID for Schizophrenia?
Adjunctive celecoxib (Celebrex) may be beneficial for treating schizophrenia.

Psychotropics and Fracture Risk
Patients (especially elderly ones) taking psychiatric medications are at increased risk for fractures.

Riluzole Augmentation for Depression
Preliminary evidence suggests riluzole (Rilutek) may be helpful in treating mood and anxiety disorders.

CBT Beats Zopiclone for Insomnia in Elderly
Cognitive behavioral therapy (CBT) was superior to zopiclone (Ambien) for chronic primary insomnia.

Alternative Medicines Are Commonly Used
Surveys show alternative medicines used by more than half of US population.

Hyponatremia with Antidepressants
Hyponatremia reported in patients treated with escitalopram (Lexapro) or duloxetine (Cymbalta).

In Brief
Dosing Strategies for Risperidone Long-Acting Injection; Deaths Associated with Methadone Treatment for Pain

Prolactin Levels and Associated Side Effects with Risperidone
Initial elevation of prolactin levels with risperidone (Risperdal) returns to normal with long-term treatment.

Mifepristone for Psychotic Depression?
Treatment with mifepristone (Mifeprex) improves psychosis but not depression in patients with psychotic depression.

rTMS: Inferior to ECT?
Repetitive transcranial magnetic stimulation (rTMS) is not as efficacious as electroconvulsive therapy (ECT) in patients referred for ECT.

Psychotropics and Fracture Risk

June 2007

Patients taking psychiatric medications may be at increased risk of fractures. This conclusion emerges from several independent studies.

Recent research suggests a role for serotonin in bone physiology. Osteoblasts and osteocytes involved in bone formation possess serotonin receptors, and serotonin is believed to modulate skeletal effects of parathyroid hormone. In mice, genetic alterations diminishing the serotonin transporter decrease skeletal mass and bone strength. Moreover, selective serotonin reuptake inhibitors (SSRIs) diminish bone gain in growing mice. Richards et al used a population-based study to investigate the effects of SSRI medications on bone density and the risk of fractures.1

The authors prospectively assessed 5008 community-dwelling adults aged 50 years and older, then followed them over 5 years. Among this sample, 137 (2.7%) used SSRIs every day.

Daily SSRI use doubled the risk of fragility bone fracture and roughly doubled the odds of falling. Bone mineral density was significantly lower at the hip, with a trend toward lower bone mineral density at the spine. These SSRI effects were dose dependent.

In a separate study, Howard and coworkers used a general practice database in the United Kingdom to analyze variables that contribute to hip fractures.2 The authors identified 16,341 cases of hip fractures and compared them to 29,889 matched controls. Taking prolactin-elevating antipsychotic drugs more than doubled the risk of a hip fracture.

Takkouche and associates performed a meta-analysis of 98 cohort and case-control studies that examined the association of psychotropic medications and fractures.3 Benzodiazepines raised the risk by 34%, antidepressants and antipsychotics by about 60%.

As people age, they are more likely to develop osteoporosis and, independently, to fall. A likely result of this combination is fractures, which are obviously painful and impair function. Some, such as hip fractures, can be fatal. Liperoti and others conducted a case control study of nursing home residents hospitalized for fractures of the femur.4 For each such case, they identified up to five control subjects who lived in the same facilities during the same time period. The sample consisted of 1787 cases and 5606 controls.

After controlling for potential confounding variables, second-generation antipsychotic use was associated with a 37% elevation in the risk of femur fracture and first-generation antipsychotics with a 35% increase. Several mechanisms may be operating. First-generation agents and, on a dose-dependent basis, risperidone (Risperdal) can cause extrapyramidal reactions and may impair gait, which could lead to more falls. Other side effects that could raise the likelihood of falling are confusion, delirium, sedation, and orthostatic hypotension. In addition, hyperprolactinemia, observed with first-generation agents and risperidone, can accelerate the loss of bone or mineral density, making a fall more likely to result in a fracture.

Elderly people often suffer from depression, which can impair function, diminish health and well-being, and decrease longevity. Depression merits treatment, which challenges clinicians to be aware of and minimize risks. For SSRIs in the elderly, these risks include bleeding, hyponatremia, and now, apparently, falls and fractures. The first-generation tricyclic antidepressants also appear to raise the potential for fractures. Benzodiazepines and other sedatives presumably make falls more likely, and antipsychotics that chronically raise prolactin levels can lead to bone thinning. Treatment decisions always involve a balancing of risks and potential benefits. This is especially so in the frail elderly.

1Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, Goltzman D, for the Canadian Multicentre Osteoporosis Study (CaMos) Research Group: Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 2007;167:188-194.

2Howard L, Kirkwood G, Leese M: Risk of hip fracture in patients with a history of schizophrenia. Br J Psychiatry 2007;190:129-134.

3Takkouche B, Montes-Martinez A, Gill SS, Etminan M: Psychotropic medications and the risk of fracture: A meta-analysis. Drug Safety 2007;30:171-184.

4Liperoti R, Onder G, Lapane KL, Mor V, Friedman JH, Bernabei R, Gambassi G: Conventional or atypical antipsychotics and the risk of femur fracture among elderly patients: Results of a case-control study. J Clin Psychiatry, in press.