*Article* **Selective Serotonin Reuptake Inhibitors for the Treatment of Depression in Adults with Down Syndrome: A Preliminary Retrospective Chart Review Study**

**Robyn P. Thom 1,2,3,†, Michelle L. Palumbo 1,2,4,†, Claire Thompson <sup>1</sup> , Christopher J. McDougle 1,2,3,\* and Caitlin T. Ravichandran 1,2,3,5**


**Abstract:** Background: Depression is a common psychiatric comorbidity in individuals with Down syndrome (DS), particularly adults, with an estimated lifetime prevalence of at least 10%. The current literature on the treatment of depression in adults with DS is limited to case series published more than two decades ago, prior to the widespread use of modern antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). The purpose of this retrospective chart review study was to examine the effectiveness, tolerability, and safety of SSRIs for depression in adults with DS. Methods: Medical records of 11 adults with DS and depression were reviewed. Assignment of scores for severity (S) of symptoms of depression and improvement (I) of symptoms with treatment with an SSRI was made retrospectively using the Clinical Global Impression Scale (CGI). Demographic and clinical characteristics of the study population, SSRI name, dose, and duration of treatment; and adverse effects were also recorded. Results: All 11 patients (7 male, 4 female; mean age = 27.2 years, range 18–46 years) completed a 12-week treatment course with an SSRI. The median duration of time after initiation of the SSRI covered by record review was 2.1 years, with a range of 24 weeks to 6.7 years. Nine of the 11 patients (82%; 95% CI 52%, 95%) were judged responders to SSRIs based on a rating of "much improved" or "very much improved" on the CGI-I after 12 weeks of treatment (median time of follow-up was 14.4 weeks, with a range of 12.0–33.0 weeks). Adverse effects occurred in four patients (36%). The most common adverse effects were daytime sedation and anger. Conclusions: In this preliminary retrospective study, the majority of patients responded to a 12-week course of SSRI treatment and some tolerated long-term use. Controlled studies are needed to further assess the efficacy, tolerability, and safety of SSRIs for the treatment of depression in adults with DS.

**Keywords:** Down syndrome; depression; selective serotonin reuptake inhibitor

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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**1. Background**

Down syndrome (DS) or trisomy 21, is a common genetic syndrome, resulting from an extra copy of chromosome 21. According to the Centers for Disease Control and Prevention, about 6000 babies are born with DS each year in the United States [1], and overall, DS occurs in about 1 in 700 live births [2]. Down syndrome commonly includes characteristic physical features, a variable degree of cognitive impairment, and several medical comorbidities. Medical comorbidities commonly associated with DS include congenital heart defects, thyroid disease, gastrointestinal problems, hematological disorders, hearing loss, ocular disorders, and obstructive sleep apnea [3]. In addition to elevated rates of medical

**Citation:** Thom, R.P.; Palumbo, M.L.; Thompson, C.; McDougle, C.J.; Ravichandran, C.T. Selective Serotonin Reuptake Inhibitors for the Treatment of Depression in Adults with Down Syndrome: A Preliminary Retrospective Chart Review Study. *Brain Sci.* **2021**, *11*, 1216. https:// doi.org/10.3390/brainsci11091216

Academic Editor: Corrado Romano

Received: 16 July 2021 Accepted: 13 September 2021 Published: 15 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

comorbidity, individuals with DS have an increased risk of psychiatric disorders compared to the general population [4–6]. Prevalence rates of psychiatric comorbidities have been reported to be as high as 38% and 35% in children and adults with DS, respectively [4,5]. Externalizing symptoms, such as oppositionality, impulsivity, and hyperactivity, are more common in children with DS, whereas internalizing symptoms, such as depression, anxiety, and social avoidance, become more prevalent in adolescence and adulthood [7–9].

Depression is a common comorbidity in adults with DS, with reported prevalence rates ranging from 6–18% [9–13]. A recent study which included 605 individuals with DS from England and Wales demonstrated that 12.4% of younger adults (16–35 years) and 18.4% of older adults (≥36 years) had a history of depression based on medical record review [13]. Females and males with DS had a four- and five-fold increased risk of depression, respectively, compared to the general United Kingdom adult population [13]. In a separate longitudinal cohort study, 134 adolescents and adults with DS (≥16 years) participated in a detailed psychiatric assessment with psychiatrists who had expertise in DS at baseline and two years later [12]. The two-year incidence of a major depressive episode in this study was 5.2% [12]. Adults with DS have several unique risk factors for developing depression compared to the general population, including cognitive impairment [14], reduced serotonin brain tissue concentration in post-mortem studies [15], high prevalence of thyroid disorders [3], and significant emotional stressors related to the transition to adulthood and loss of school-based programming and services.

Depression is often underrecognized and undertreated in adults with DS. There are several diagnostic challenges related to the inherent communicative and cognitive limitations. While the clinical characteristics of depression in individuals with DS are often similar to those seen in the general population, including sad mood, anhedonia, decreased appetite and weight loss, social withdrawal, reduced speech, low energy, and psychomotor slowing [6], individuals with DS may have difficulty expressing depressive cognitions such as guilt, worthlessness, self-deprecation, or thoughts of suicide [10]. These clinical features may necessitate taking into account behavioral observations and caregiver reports rather than strict application of diagnostic criteria. A retrospective study assessing the clinical features of depression in DS reported that when strict Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R) criteria were applied, only 50% of depressive episodes diagnosed by expert clinicians met the full criteria [10]. This study also demonstrated that depression was frequently misdiagnosed as dementia in individuals with DS and therefore left untreated [10]. In a retrospective study of 42 adults with DS, not all patients with depression received pharmacotherapy, and no patients received a second medication trial if the first was ineffective [10], suggesting undertreatment of a generally treatable psychiatric comorbidity.

Data on effective treatment approaches for depression in DS are lacking, and systematic studies on the treatment of depression have been highlighted as a critically needed area of research [16]. The published literature on pharmacotherapy for depression in DS is limited to case reports and case series [6]. No systematic studies on the effectiveness, tolerability, and safety of antidepressants in DS have been published. Three case series were published more than 20 years ago, prior to the widespread use of modern antidepressants, reporting the clinical response to tricyclic antidepressants (TCAs) [17–19] and one of these case series also reported on three patients' response to fluoxetine, a selective serotonin reuptake inhibitor (SSRI) [18]. All three patients who received treatment with fluoxetine had a positive response, two of whom had previously failed to respond to TCAs. Of the remaining six patients described in this case series, three other patients responded to TCAs, one responded to a first-generation antipsychotic, and two did not receive pharmacologic treatments. Medication side effects are not reported in any of these case series.

Selective serotonin reuptake inhibitors are a class of medications which include fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram. They selectively block the uptake of serotonin and have several Food and Drug Administration (FDA) indications, including for the treatment of depression, anxiety disorders, obsessive-compulsive

disorder, and posttraumatic stress disorder. Selective serotonin reuptake inhibitors have largely replaced the TCAs as the first-line treatment for depressive disorders due to similar efficacy, improved tolerability, and a much safer side effect profile [20]. Unlike TCAs, SSRIs are generally nonlethal in overdose, are not associated with cardiac toxicity, and do not lower the seizure threshold. Modern clinical practice guidelines include SSRIs among the first-line medications for the treatment of depression [21]. Tricyclic antidepressants are considered second-line medications, only to be used after the failure of one or more first-line medications [21]. In clinical practice, SSRIs are typically the first class of medications used to treat depression. A recent study demonstrated that SSRIs comprised 93% of first-line medications for depression in primary care [22]. Selective serotonin reuptake inhibitors have a relatively benign side effect profile and are generally well tolerated. The most common side effects include impaired sexual functioning, sleepiness, and weight gain; 25% of patients consider side effects to be either "very bothersome" or "extremely bothersome" [23]. Despite the widespread use of SSRIs in the general population, their use in patients with DS has only been reported in three patients in a single case series [18].

This study aims to provide preliminary naturalistic data on whether treatment with SSRIs is effective, tolerable, and safe in reducing depression symptoms in adults with DS.
