04. Long-Term Effects of Lithium Use on Children and Adolescents

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Hi! David Rosenberg here for the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will look at a study examining lithium’s long-term safety and effectiveness in children and adolescents with bipolar and nonbipolar conditions. This is a retrospective study conducted in Turkey on 143 patients 9–18 years of age. About 70% had a diagnosis of bipolar disorder, and 30% a diagnosis of a nonbipolar condition, which included major depressive disorder, schizoaffective disorder, ADHD, conduct disorder, severe mood dysregulation syndrome, borderline personality disorder, and autism.

This is important and timely because lithium was the first FDA-approved medication for pediatric bipolar disorder. It is also commonly used for other conditions. However, there has been a fear factor regarding its use because of what I call “the PIN effect.” And you might ask what is the PIN effect—P-I-N. It is a pain in the neck factor that patients, families, and clinicians feel with all the laboratory monitoring, clinical follow-up, and potential side effects. However, I think it is worthy of further study, particularly long-term lithium use because it is such a potent mood-stabilizing agent, and to begin to look at what is real, what is perceived, and what is the actual clinical utility of long-term lithium use.

So, what did the authors of this study find? First and not surprisingly, patients with bipolar disorder had more adverse events than patients with nonbipolar disorder conditions. In addition, many of us have had a fear and concern about needing to monitor kidney function and the possibility of renal failure and renal complications on lithium. Moreover, this study observed a statistically significant increase in serum creatine in the third and 12th month of treatment. However, it is important to note that this statistically significant increase in serum creatine did not exceed the normal laboratory range; that is, there were no serum creatine abnormalities reported at all. So, the increase was in the normal creatine laboratory range, which is important because it suggests that we can safely treat our patients as long as we closely monitor for renal failure.

So, why continue to monitor for renal failure if all patients had creatine levels within the normal limit in this series of patients? Even though it is a statistically significant increase, and we do not precisely know whether that translates clinically, the fact that there is an increase raises the question about its impact on the glomerular filtration rate (GFR). So, we would still advise monitoring very closely for renal failure but recognizing that it appears to be a rare effect, particularly in otherwise medically healthy patients treated with lithium.

There was also a statistically significant increase in white blood cell counts at all times patients were evaluated. White blood cell counts exceeded 13,000 in about 10% of the patients. However, this should not be surprising because benign leukocytosis has long been recognized with lithium. Furthermore, this study found that the increase did not exceed 1 and one-half times normal, which is not clinically significant.

While doing my psychiatry residency, I consulted on a patient with multiple medical problems. One of the concerns was this unexplained leukocytosis. The attending whom I was working with immediately picked up on the fact that the patient was on lithium and noted that this was most likely a benign leukocytosis. So, you can see how it is clinically relevant to recognize the benign leukocytosis associated with lithium.

Another point of interest is that lithium in children and adolescents has been used successfully in neutropenia associated with clozapine treatment. So, again, all kinds of potential value for lithium treatment.

I want to mention that the authors found a statistically significant increase in thyroid stimulating hormone, or TSH levels. Thus, thyroid function is something we have long known can be associated with lithium treatment, which is why it is essential to monitor thyroid function. In this study, nearly 30% of patients treated with lithium had TSH levels exceeding 5.5 mU/L. The authors also found that higher basal TSH levels, longer duration of lithium treatment, higher lithium dose, and higher lithium serum levels were associated with further increases in TSH levels and the need for thyroid hormone replacement therapy or thyroxine treatment. Fifteen percent of the patients with TSH elevation needed thyroxine replacement therapy, as recommended by an endocrinologist.

The mean lithium dose, as expected, was higher in the bipolar group compared with the nonbipolar group, where lithium was more often used as an adjunct. Interestingly, mean serum lithium levels did not differ between patients with bipolar disorder and nonbipolar conditions. Almost all patients were also on antipsychotic medications, so weight gain and increased appetite were not considered lithium-specific side effects.

There were some limitations in this particular study. Patients were on other psychotropic medicines, such as antipsychotics, as well as other medications. However, I see that as a strength of this particular study because it makes it more generalizable to what those who treat children and adolescents with bipolar disorder see: Polydrug therapy is the rule rather than the exception.

So, the bottom line here is that lithium was generally safe and effective for children and adolescents with bipolar and nonbipolar conditions. Very close monitoring is needed for thyroid function, especially for those with higher basal TSH levels, who have been on lithium for extended periods, who require higher doses of lithium, and with higher lithium blood levels.

Abstract

Long-Term Effects of Lithium Use on Children and Adolescents: A Retrospective Study from Turkey

Hatice Güneş, Canan Tanıdır, Hilal Doktur, Gül Karaçetin, Ali Güven Kılıçoğlu, Özhan Yalçın, Mustafa Kayhan Bahalı, Caner Mutlu, Özden Şükran Üneri, Ayten Erdoğan

Background: The aim of this study was to evaluate the long-term effects of lithium treatment on white blood cell (WBC) count, serum creatinine, and thyroid-stimulating hormone (TSH) levels in children and adolescents with bipolar disorder (BD) and non-BD in a Turkish children and adolescent sample.

Methods: The study is based on retrospective chart review. Children and adolescent patients with BD and non-BD prescribed lithium in a mental health and neurological disorders hospital between 2012 and 2017 were included in the study. Data were collected from the electronic medical files. Laboratory values for WBC count, serum creatinine, and TSH levels at baseline within the week before the onset of lithium, and at 1st, 3rd, 6th , and 12th month of treatment were recorded.

Results: A total of 143 patients (82 females, 61 males; 100 BD, 43 non-BD) aged 9-18 were included. Non-BD diagnoses were psychotic and schizoaffective disorders, unipolar depression, attention-deficit/hyperactivity disorder, conduct disorder, severe mood dysregulation syndrome, borderline personality disorder, and autism. Mean age of the participants were 15.90 ± 1.16 years for the bipolar group and 14.88 ± 1.79 years for the nonbipolar group. Patients with BD reported more adverse effects. There was a statistically significant increase in WBC counts and TSH levels at any time point. A statistically significant elevation in serum creatinine was found at 3rd and 12th month of treatment. During the course of lithium treatment, WBC counts exceeded 13,000 in 14 (9.8%) patients, and TSH levels exceeded 5.5 mU/L in 41 patients (28.6%). Twenty-one (14.68%) patients were started on thyroxin replacement. Basal TSH levels and duration of the lithium treatment were higher in the participants with TSH levels exceeding 5.5 mU/L. Lithium maximum dose, lithium blood level, basal TSH level, and duration of treatment were higher in the participants receiving thyroxin replacement. No patients had serum creatinine levels exceeding the normal reference values.

Conclusion: Our study suggests that lithium is a generally safe and tolerable agent for children and adolescents with BD and non-BD; however, close monitoring of thyroid functions particularly in patients with a higher basal TSH level and longer duration of lithium use is important.

Reference

Güneş, H., Tanıdır, C., Doktur, H., Karaçetin, G., Kılıçoğlu, A. G., Yalçın, Ö., Bahalı, M. K., Mutlu, C., Üneri, Ö. Ş., & Erdoğan, A. (2022). Long-term effects of lithium use on children and adolescents: A retrospective study from Turkey. Journal of Child and Adolescent Psychopharmacology, 32(3), 162-170.