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Letters to the Editor   |    
Risperidone-Associated Hypocalcemia
Dragan R. Milovanovic, M.D., Ph.D.; Vladimir Janjic, M.D., M.Sc.; Nenad Zornic, M.D., M.Sc.; Slavica Djukic Dejanovic, M.D., Ph.D.; Slobodan M. Jankovic, M.D., Ph.D.
Am J Psychiatry 2010;167:1533-1534. doi:10.1176/appi.ajp.2010.10071003
View Author and Article Information
Kragujevac, Serbia

The authors report no financial relationships with commercial interests.

The authors thank V. Janjic, N. Zornic, and their associates for collecting study data.

This letter was accepted for publication in September 2010.

Accepted September , 2010.

Copyright © American Psychiatric Association

To the Editor: Drug-induced electrolyte disturbances have considerable implications. In our recent research dealing with this topic (1), an association between hypocalcemia and drug treatment was noted in a small subset of risperidone users. We then retrieved all medical files in our psychiatry clinic and examined adult patients with at least one measurement of serum calcium, regardless of diagnosis/drug therapy, excluding those with obvious risks for electrolyte disturbances.

Finally, 1,320 record sets were derived from 1,245 patients (see the data supplement accompanying the online version of this letter). Risperidone users had more frequent incidence of hypocalcemia (≤2.1 mmol/l) (N=50/328) than comparison subjects (N=19/973) (odds ratio=9.21, 95% confidence interval [CI]=5.34—15.88, χ2=88.4, df=1, p<0.001). The mean calcemia level was significantly lower in the risperidone group (2.24 mmol/l [SD=0.13] vs. 2.33 mmol/l [SD=0.12], t=−11.7, df=1318, p<0.001). Additionally, there was significant correlation between the risperidone dose (mean daily dose: 2.5 mg [SD=1.2], 95% CI=2.4—2.8) and the serum calcium level (F=98.8, df=1, p<0.001; rs=−0.299, p<0.001), with the lowest concentrations at approximately 3 mg (Figure 1). Multivariable logistic regression, with confounders well-documented in the source data (age, gender, current drug treatment, data sets) (see the data supplement), confirmed independent association of risperidone and hypocalcemia (adjusted odds ratio=9.21, 95% CI=5.02—17.81, df=1, p<0.001). Both in the total number of hypocalcemic subjects (N=73) and in those with hypocalcemia within 99 percentiles (N=69), no significant association with any other study variable was found.

 
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FIGURE 1.

Correlation Between Risperidone Daily Dose and Serum Calcium Levels in Adult Patients

Presently, it is not known whether the association has causal relationships. In addition, our method does have some shortcomings (e.g., possibility of selection bias), although we utilized a fairly large sample size, with the finding being stable on different statistics. However, correlation of calcemia level with risperidone dose and literature data probably justifies additional research of possible causality. Risperidone, as well as other antipsychotics, can induce hyperprolactinemia and hypogonadism (2), synthesis of calcium binding proteins in the tissues (3), and changes in calcium-dependent signaling pathways (4), which could cause a calcium-depleted state and/or trigger calcium redistribution within body compartments. Individuals treated with antipsychotics have small but variable risks of hip fracture (5). With additional risks, even small disturbances of calcium homeostasis could make this population prone to osteoporosis and increase the probability of fractures.

Zornic  N;  Radojevic  DJ;  Jankovic  S;  Djuric  D;  Varjacic  M;  Simic  VD;  Milovanovic  DR:  Monitoring of drug-associated electrolyte disturbances in a hospital.  Pharmacoepidemiol Drug Saf 2009; 18: 1026—1033
[CrossRef] | [PubMed]
 
Kishimoto  T;  Watanabe  K;  Shimada  N;  Makita  K;  Yagi  G;  Kashima  H:  Antipsychotic-induced hyperprolactinemia inhibits the hypothalamo-pituitary-gonadal axis and reduces bone mineral density in male patients with schizophrenia.  J Clin Psychiatry 2008; 69: 385—391
[CrossRef] | [PubMed]
 
Quincozes-Santos  A;  Abib  RT;  Leite  MC;  Bobermin  D;  Bambini-Junior  V;  Gonçalves  CA;  Riesgo  R;  Gottfried  C:  Effect of the atypical neuroleptic risperidone on morphology and S100B secretion in C6 astroglial lineage cells.  Mol Cell Biochem 2008; 314: 59—63
[CrossRef] | [PubMed]
 
Rushlow  WJ;  Seah  C;  Sutton  LP;  Bjelica  A;  Rajakumar  N:  Anti-psychotics affect multiple calcium calmodulin dependent proteins.  Neuroscience 2009; 161: 877—886
[CrossRef] | [PubMed]
 
Liperoti  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 2007; 68: 929—934
[CrossRef] | [PubMed]
 
References Container

FIGURE 1. 

Correlation Between Risperidone Daily Dose and Serum Calcium Levels in Adult Patients

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References

Zornic  N;  Radojevic  DJ;  Jankovic  S;  Djuric  D;  Varjacic  M;  Simic  VD;  Milovanovic  DR:  Monitoring of drug-associated electrolyte disturbances in a hospital.  Pharmacoepidemiol Drug Saf 2009; 18: 1026—1033
[CrossRef] | [PubMed]
 
Kishimoto  T;  Watanabe  K;  Shimada  N;  Makita  K;  Yagi  G;  Kashima  H:  Antipsychotic-induced hyperprolactinemia inhibits the hypothalamo-pituitary-gonadal axis and reduces bone mineral density in male patients with schizophrenia.  J Clin Psychiatry 2008; 69: 385—391
[CrossRef] | [PubMed]
 
Quincozes-Santos  A;  Abib  RT;  Leite  MC;  Bobermin  D;  Bambini-Junior  V;  Gonçalves  CA;  Riesgo  R;  Gottfried  C:  Effect of the atypical neuroleptic risperidone on morphology and S100B secretion in C6 astroglial lineage cells.  Mol Cell Biochem 2008; 314: 59—63
[CrossRef] | [PubMed]
 
Rushlow  WJ;  Seah  C;  Sutton  LP;  Bjelica  A;  Rajakumar  N:  Anti-psychotics affect multiple calcium calmodulin dependent proteins.  Neuroscience 2009; 161: 877—886
[CrossRef] | [PubMed]
 
Liperoti  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 2007; 68: 929—934
[CrossRef] | [PubMed]
 
References Container
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Monitoring of drug-associated electrolyte disturbances in a hospital. Pharmacoepidemiol Drug Saf 2009;18(11):1026-33.
Risperidone-associated hypocalcemia. Am J Psychiatry 2010;167(12):1533-4.