Abstract
Objectives:
Treatment with selective serotonin reuptake inhibitors (SSRIs) is common and is considered safe and effective in the treatment of anxiety and depressive disorders in pediatric populations. SSRI administration, however, is associated with adverse metabolic effects. The aim of this preliminary study was to evaluate the possible influence of a 6-month SSRI treatment on metabolic parameters in children and adolescents with depressive and/or anxiety disorders.
Methods:
Metabolic parameters (glucose, cholesterol, triglycerides, low-density lipoprotein [LDL], and high-density lipoprotein [HDL]) were monitored in 22 children and adolescents (16 boys and 6 girls, aged 8–18 years) at baseline and after 6 months of SSRI treatment for depression and/or anxiety.
Results:
Six months of SSRI treatment did not affect serum glucose, cholesterol, or triglycerides significantly, but a tendency (p = 0.06) toward elevation in serum LDL accompanied by a parallel reduction in HDL levels was detected.
Conclusion
: It appears that the 6-month SSRI treatment is metabolically safe in children and adolescents and does not affect the glucose or lipid profile. Long-term large-scale studies in pediatric populations focusing on the possible impact of long-term SSRI treatment (>6 months) on metabolic parameters are warranted.
Introduction
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While SSRIs are safer and much better tolerated than the old tricyclic antidepressants, they still possess a wide range of side effects. In addition to side effects resulting from short-term treatment, there are some resulting from long-term treatment (Masand and Gupta 2002). Those include sexual dysfunction, gastrointestinal symptoms, withdrawal symptoms, and complicated drug–drug interactions. It seems that long-term treatment with SSRIs may affect the human metabolism, including lipid metabolism, glucose levels, and body weight (Brown et al. 2008).
Raeder et al. (2006) studied the association between glucose, dyslipidemia, and weight gain and SSRI treatment. It was found that among patients suffering from depression and those who are medicated, the rate of overweight and hypercholesterolemia is higher than among those who are not medicated. It was also found that the SSRI paroxetine is associated with weight gain and cholesterol increase more often than other SSRIs. Still, other SSRIs such as fluoxetine, fluvoxamine, and sertraline were associated with weight gain and cholesterol increase, but the association was significantly weaker than that of paroxetine.
In other epidemiological studies that were done in adults suffering from depression and medicated with SSRIs, it was found that some showed an increase in glucose, cholesterol, and triglyceride blood levels. Due to the strong association evidenced between treatment with SSRIs and metabolic changes and weight gain, the authors recommended follow-up and repeated monitoring of lipids, glucose, and weight of patients maintained on long-term SSRI treatment (Raeder et al. 2006).
According to reports, in recent years, SSRI use in pediatric populations is on the rise. A number of large-sample clinical studies demonstrated the efficacy of SSRIs in treating children and adolescents, including those suffering from depression, anxiety, and obsessive-compulsive disorder (Brown et al. 2008; Briscoe et al. 2008). Despite the reported safety of these medications and their clear advantage over the old tricyclic medications with regard to side effects, some side effects similar to those described in adults are still present (Schirm et al. 2001; Zuckerman et al. 2007; Alacqua et al. 2008). A recent review demonstrated that SSRI treatment in adults may be associated with deleterious effects on metabolic parameters, including increase in cholesterol and triglyceride blood levels (Chávez-Castillo et al. 2018).
Little is known about the effect of these medications on lipid metabolism, glucose level, and weight in children and adolescents. To the best of the authors' knowledge, no studies investigating the effects of long-term treatment with SSRIs on metabolic indices in children have been published yet. During a study to assess the tolerability of SSRIs in children and adolescents, Alacqua et al. (2008) found that about 21% of patients who were treated with paroxetine reported various side effects, including weight gain (Alacqua et al. 2008). Since (as mentioned earlier) it seems that the long-term effects of SSRIs in children and adolescents have not been investigated as yet, the aim of the current study is to use a computerized database to investigate the metabolic effects of SSRIs in this population.
Objective
The aim of the study was to assess whether long-term SSRI treatment in children and adolescents results in metabolic changes, including changes in the lipid levels, glucose levels, and influence on body weight.
Importance
The results of this study may provide caretakers with a better understanding of the effects, on the lipid profile and glucose levels of pediatric populations, of long-term SSRI treatment. It aims to provide tools for the assessment of risk levels of such treatments and to enable more informed decision-making regarding treatment. It will help formulate some safety rules for cases of anomalous results and may lead, for example, to the decision to perform regular tests and follow-up of metabolic changes (serum lipid and glucose levels and regular monitoring of body weight). In summary, the aim of this preliminary study was to evaluate the possible influence of a 6-month SSRI treatment on metabolic parameters in children and adolescents with depressive and/or anxiety disorders.
Methods
Population
The study included boys (n = 16) and girls (n = 6), aged 8–18 years, who received SSRI treatment for depression and/or anxiety for the first time in their lives. The patients were diagnosed by a senior child and adolescent psychiatrist within the setting of the Geha Mental Health Center outpatient clinic. The diagnoses were established according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; American Psychiatric Association, 2000) criteria.
The following were excluded from the study: patients suffering from diabetes, obesity, hereditary dyslipidemia; patients receiving treatment to lower lipid levels; and patients with a history of psychotic disorders.
All participants and their parents signed an informed consent form after the nature of the study was explained to them. The study received approval from the Geha Mental Health Center's Ethics Review Board.
Medications
Medications that were investigated were fluoxetine and fluvoxamine, both of which are approved as safe SSRIs by the Israeli Child and Adolescent Psychiatric Association. Both are known to be effective for treating anxiety and depression in pediatric populations. None of the subjects received antipsychotics or mood stabilizers during the follow-up.
Blood tests
Blood samples after overnight fasting were collected twice—at the start of the study, before initiation of the drug treatment, and again 6 months later. Blood levels of triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and glucose were determined. The ranges considered normal, that is, safe and desirable, in this study were LDL below 130 mg/dL; HDL above 40 mg/dL; glucose 70–110 mg/dL; cholesterol less than 200 mg/dL; and triglycerides below 150 mg/dL.
Statistical analysis
The results were analyzed by a paired t test, χ 2 test, or Fisher's exact test as appropriate and Bonferroni correction as needed.
Results
Study population
Sixteen boys and 6 girls, aged 8–17 years (mean = 13.04, SD = 2.5 years), participated in the study. All were treated with fluoxetine (20–40 mg/day).
Glucose levels before and during SSRI treatment
No significant differences were found in the 22 participants between pre- and post-SSRI treatment glucose levels (83.1 ± 11.9 vs. 87.5 ± 13.0 mg/dL, respectively; paired t = 0.49, df = 21, two-tailed p = 0.63, not significant [NS]).
Lipid levels before and during SSRI treatment
Triglycerides
No significant differences were found between pre-SSRI treatment triglyceride levels and post-treatment levels (n = 20), (86.1 ± 40.4 vs. 89.4 ± 44.3 mg/dL; paired t = 0.37, df = 19, p = 0.71, NS).
Total cholesterol
No significant differences were found between pre-SSRI treatment cholesterol levels and post-treatment levels (n = 21), (163.6 ± 32.5 vs.161.9 ± 27.6 mg/dL; paired t = 0.31, df = 20, p = 0.76, NS).
High-density lipoprotein
Findings showed a trend toward reduction of HDL levels following SSRI treatment (n = 18), (53.4 ± 8.9 vs. 50.1 ± 10.9 mg/dL; paired t = 1.97, df = 17, p = 0.06, NS).
Low-density lipoprotein
LDL levels showed a trend to increase following SSRI treatment (n = 18), (89.8 ± 31.2 vs. 98.7 ± 22.2 mg/dL; paired t = 2.05, df = 17, p = 0.06, NS).
Discussion
The present preliminary study demonstrated that long-term (6 months) treatment of children and adolescents (aged 8–18 years) with SSRIs for anxiety and/or depressive disorders does not significantly affect metabolic parameters, including serum glucose and lipid profiles. There was, however, a tendency toward elevation in serum LDL, accompanied by a parallel reduction in HDL levels, but these changes were within the normal range. SSRI-induced elevation in serum lipids in childhood or adolescence may precede dyslipidemia and constitute an increased risk for cardiometabolic diseases (Beyazyuz et al. 2013; Hiles et al. 2016).
It is of note that a recent study found that in young people (aged 5–20 years) treated with SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs) for more than 150 days, the risk of type 2 diabetes was 2.5-fold higher than in those who received similar treatment for only 1–90 days. The risk of type 2 diabetes also rose with increasing average daily doses of SSRIs or SNRIs (Burcu et al. 2017). The current study investigated children and adolescents of similar age range, who were treated with SSRIs for 6 months, but failed to detect iatrogenic metabolic changes. It is, however, possible that longer duration and larger doses are needed to induce significant persistent elevation in serum glucose and/or lipids.
The major limitations of this study are the small sample size, small range of doses, and relatively short duration of follow-up (6 months). Another drawback is the lack of data about corresponding alterations in BMI. In contrast to the numerous studies about adverse metabolic effects of SSRIs in adult psychiatric patients (Uguz et al. 2015; Fjukstad et al. 2016; Marijnissen et al. 2017; Olguner Eker et al. 2017), the paucity of data on such adverse effects of SSRIs in pediatric populations is notable. To the best of the authors' knowledge, only few studies exist on the impact of SSRIs on metabolic parameters in children and adolescents, in contrast to relatively abundant data on atypical antipsychotics and mood stabilizers (Correll and Carlson 2006). Some studies demonstrated that SSRI treatment in pediatric populations was associated with weight gain, but no data on metabolic parameters were reported (Mansoor et al. 2013).
Conclusion
Long-term large-scale studies focusing on the possible impact of SSRIs on both BMI and metabolic parameters in pediatric populations are warranted.
Clinical Significance
Despite the scarce data on the metabolic effects of SSRIs in pediatric populations, both clinicians and parents should be aware of potential metabolic adverse effects of SSRIs.
Disclosures
None of the authors report any conflict of interests with regard to this study. Prof. Abraham Weizman presented a few educational lectures sponsored by Medison and Novartis on the topic of attention-deficit/hyperactivity disorder. Those lectures are completely unrelated to this article.