*3.4. Response to SSRI Treatment*

All 11 patients completed at least a 12-week course of SSRI treatment. The median duration of the follow-up period from time of SSRI treatment initiation to the end of the 12-week treatment course was 14.4 weeks, with a range of 12.0–33.0 weeks. Clinical Global Impression ratings before and after 12 weeks of treatment are presented in Figure 2. Based on the CGI-I rating for the soonest psychiatric visit after 12 weeks of treatment, nine of the 11 patients responded (response rate 82%; 95% CI 52%, 95%), with three patients rated as very much improved (CGI-I = 1) and six patients rated as much improved (CGI-I = 2). Eight of the 11 patients (73%) were rated as mildly ill or less at follow-up (CGI-S ≤ 3), with five patients rated as mildly ill (CGI-S = 3), two patients rated as borderline mentally ill (CGI-S = 2), and one patient rated as not at all ill (CGI-S = 1). One of the remaining three patients, taking fluoxetine, was much improved (CGI-I = 2) but still moderately ill (CGI-S = 5); one taking fluoxetine was minimally improved (CGI-I = 3) and still moderately ill (CGI-S = 4); and one taking sertraline was minimally worse (CGI-I = 5) and severely ill (CGI-S = 6). Of the three patients who had previously been prescribed an SSRI, two of the patients were responders (CGI-I = 1 or 2).

Table 3 summarizes the long-term treatment course beyond the initial 12 weeks of treatment 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. Seven patients (64%) had a sustained positive response to the SSRI until the most recent follow-up, and one patient (9%) had a positive response to fluoxetine and was able to discontinue it after three years of stability without a return of depression. Three patients (27%) had an initially positive response to the SSRI but later experienced either behavioral activation or mania with sustained treatment. Of these three patients, two patients (18%) experienced behavioral activation (irritability, anger, and/or agitation) when the SSRI was titrated to a certain dose (escitalopram 15 mg daily and fluoxetine 20 mg daily). The third patient experienced a manic episode after six months of treatment with fluoxetine 15–20 mg daily. Three patients were optimally managed on the SSRI plus an adjunctive medication, either aripiprazole (a second-generation antipsychotic) [*n* = 2], or buspirone (a serotonin-1A partial agonist) [*n* = 1].

**Figure 2.** Clinical Global Impression Severity Scale (CGI-S) scores at the initiation of SSRI treatment and at first follow-up visit following 12 weeks of treatment. Each line represents the change in CGI-S score for one patient. Line color corresponds to SSRI: green = fluoxetine, blue = sertraline, orange = escitralopram. Color of marker at follow-up corresponds to CGI-Improvement scale (CGI-I) score: pink = very much improved (CGI-I = 1), yellow = much improved (CGI-I = 2), purple = minimally improved (CGI-I = 3), gray=minimally worse (CGI-I = 5). **Figure 2.** Clinical Global Impression Severity Scale (CGI-S) scores at the initiation of SSRI treatment and at first follow-up visit following 12 weeks of treatment. Each line represents the change in CGI-S score for one patient. Line color corresponds to SSRI: green = fluoxetine, blue = sertraline, orange = escitralopram. Color of marker at follow-up corresponds to CGI-Improvement scale (CGI-I) score: pink = very much improved (CGI-I = 1), yellow = much improved (CGI-I = 2), purple = minimally improved (CGI-I = 3), gray=minimally worse (CGI-I = 5).

Figure 3 presents results on the duration of medication use. Four patients (36%) discontinued use of SSRI medications in the period covered by psychiatric notes in the medical record: three (at 24 weeks, 31 weeks, and 2.1 years, respectively) because of both loss of effectiveness and difficulty tolerating the medication and one (at 3.1 years) because the medication was no longer needed. The duration of medication use at the time of the most recent psychiatric note for the seven patients who remained on medication ranged from 33 weeks to 6.7 years. For the two patients remaining on sertraline, the doses at the time of last follow-up note were 62.5 mg and 125 mg daily. For the five patients remaining on fluoxetine, mean (SD) final dose was 26.8 (24.3) mg per day, with a range of 14.0–70.0 mg per day. Overall, 9/11 patients (82%; 95% CI 52%, 95%) achieved remission (≥3 weeks of minimal depressive symptoms), and 8/11 patients (73%; 95% CI 43%, 90%) achieved re-Figure 3 presents results on the duration of medication use. Four patients (36%) discontinued use of SSRI medications in the period covered by psychiatric notes in the medical record: three (at 24 weeks, 31 weeks, and 2.1 years, respectively) because of both loss of effectiveness and difficulty tolerating the medication and one (at 3.1 years) because the medication was no longer needed. The duration of medication use at the time of the most recent psychiatric note for the seven patients who remained on medication ranged from 33 weeks to 6.7 years. For the two patients remaining on sertraline, the doses at the time of last follow-up note were 62.5 mg and 125 mg daily. For the five patients remaining on fluoxetine, mean (SD) final dose was 26.8 (24.3) mg per day, with a range of 14.0–70.0 mg per day. Overall, 9/11 patients (82%; 95% CI 52%, 95%) achieved remission (≥3 weeks of minimal depressive symptoms), and 8/11 patients (73%; 95% CI 43%, 90%) achieved recovery (≥4 months of minimal depressive symptoms) based upon the most recent psychiatric follow-up note.

### atric follow-up note. *3.5. Adverse Effects*

Four of the 11 patients (36%; 95% CI 15%, 65%) had adverse effects reported in their psychiatric notes. Daytime sedation and anger were reported for two patients (18%) each, and weight gain, behavioral activation, irritability, anxiety, and mania were reported for one patient (9%) each. There was no indication of increased suicidal thinking, intent, plan, or attempts in any of the psychiatric follow-up notes.

covery (≥ 4 months of minimal depressive symptoms) based upon the most recent psychi-

**Figure 3.** Proportion of patients remaining on SSRI medication over time. Tick-marks correspond to time of last psychiatric note for patients who remained on an SSRI at most recent psychiatric visit. **Figure 3.** Proportion of patients remaining on SSRI medication over time. Tick-marks correspond to time of last psychiatric note for patients who remained on an SSRI at most recent psychiatric visit.

### *3.5. Adverse Effects* **4. Discussion**

Four of the 11 patients (36%; 95% CI 15%, 65%) had adverse effects reported in their psychiatric notes. Daytime sedation and anger were reported for two patients (18%) each, and weight gain, behavioral activation, irritability, anxiety, and mania were reported for one patient (9%) each. There was no indication of increased suicidal thinking, intent, plan, or attempts in any of the psychiatric follow-up notes. **4. Discussion**  This naturalistic, retrospective study evaluated the real-world effectiveness and tolerability of SSRIs for the treatment of depressive disorders in a small sample of adults with DS. This study reports on the largest sample of individuals with DS treated with SSRIs to date. It also offers insight into how SSRIs are used in a long-term naturalistic tertiary care clinical setting. This study informs on several issues that have not been previously reported in adults with DS, including the clinical characteristics of those receiving treatment with SSRIs, the initial 12-week response rate to SSRIs, long-term tolerability of SSRIs, long-term response, and adverse effects. Selective serotonin reuptake inhibitors are This naturalistic, retrospective study evaluated the real-world effectiveness and tolerability of SSRIs for the treatment of depressive disorders in a small sample of adults with DS. This study reports on the largest sample of individuals with DS treated with SSRIs to date. It also offers insight into how SSRIs are used in a long-term naturalistic tertiary care clinical setting. This study informs on several issues that have not been previously reported in adults with DS, including the clinical characteristics of those receiving treatment with SSRIs, the initial 12-week response rate to SSRIs, long-term tolerability of SSRIs, long-term response, and adverse effects. Selective serotonin reuptake inhibitors are the most commonly prescribed first-line medications for depression in the general population. Previous studies of pharmacotherapy for depression in adults with DS have predominantly reported on TCAs, which are now reserved for treatment-refractory depression in modern psychopharmacology due to the potential for life-threatening adverse effects. The results from this study suggest that the treatment of depression in DS with SSRIs was overall well tolerated and safe, and was associated with clinically significant improvement in symptoms of depression in most adults with DS; however, prospective randomized controlled trials are needed to provide conclusive evidence.

the most commonly prescribed first-line medications for depression in the general population. Previous studies of pharmacotherapy for depression in adults with DS have predominantly reported on TCAs, which are now reserved for treatment-refractory depression in modern psychopharmacology due to the potential for life-threatening adverse effects. The results from this study suggest that the treatment of depression in DS with SSRIs was overall well tolerated and safe, and was associated with clinically significant improvement in symptoms of depression in most adults with DS; however, prospective randomized controlled trials are needed to provide conclusive evidence. In this study, a majority (82%; 95% CI 52%, 95%) of patients responded to SSRI therapy (CGI-I ≤ 2). This response rate is similar to the data reported in a retrospective study conducted by Myers et al. [18]. Myers et al. reviewed the records of 164 adults treated as In this study, a majority (82%; 95% CI 52%, 95%) of patients responded to SSRI therapy (CGI-I ≤ 2). This response rate is similar to the data reported in a retrospective study conducted by Myers et al. [18]. Myers et al. reviewed the records of 164 adults treated as outpatients from 1979–1989 in the Down Syndrome Program at the Child Development Center at Rhode Island Hospital and identified nine adults with a depressive disorder, three of whom were treated with an SSRI (fluoxetine). All three patients (100%) who received treatment with fluoxetine (mean dosage: 47 mg per day) were deemed responders [18]. No other reports on the use of SSRIs for depression in DS have been published. Data from our study also indicate that the majority of patients achieved long term response, as indicated by the 82% (95% CI 52%, 95%) remission or recovery rate. This high rate of remission or recovery demonstrates the overall treatability of depression in DS, underscoring the importance of accurate case detection and availability of treatment.

outpatients from 1979–1989 in the Down Syndrome Program at the Child Development Center at Rhode Island Hospital and identified nine adults with a depressive disorder, Findings from this study also suggest that psychotic features may be commonly associated with depression in DS. Two of the 11 patients (18%; 95% CI 5%, 48%) in this

three of whom were treated with an SSRI (fluoxetine). All three patients (100%) who re-

sample experienced depression with psychotic features. One patient complained of hearing voices, was observed to be responding to internal stimuli, and exhibited disorganized behaviors, such as trying to leave the house in the middle of the night without clothing. The other patient experienced auditory hallucinations of derogatory content, which resulted in distress manifesting as pushing, screaming, and looking for knives as well as paranoid delusions of people breaking into the house. Both patients were successfully treated with a combination of fluoxetine and aripiprazole (a second-generation antipsychotic). Previous literature also supports an elevated rate of depression with psychotic features in DS. A study including 49 adolescents and young adults (13–29 years) treated in specialized psychiatric clinics reported that 8% of patients with DS had a history of depression with psychotic features [11]. Another study comparing the prevalence of obstructive sleep apnea in adults with DS with or without depression reported that 9/28 (32%) patients in the depression group had accompanying psychotic features [27].

Patients in this study generally responded to lower dosages of SSRIs than is typically used in the general population [28]. The mean starting dosage of fluoxetine was 4.9 mg daily and the mean maximal dosage was 25.5 mg daily, which approximates the recommended starting dosage of 20 mg daily in the general adult population [28]. This dosing strategy differs from the three cases reported by Myers et al., in which more typical adult dosing was used (optimal dosages of 20 mg, 40 mg, and 80 mg daily) [18]. Especially in light of the observation that two patients (18%) in our study experienced behavioral activation at a certain dosage threshold (fluoxetine 20 mg and escitalopram 15 mg daily) and a third experienced a manic episode after six months of treatment with fluoxetine 15–20 mg daily, the results from this study support a more conservative dosing strategy.

Although SSRIs were generally well tolerated, four of the 11 patients (36%; 95% CI 15%, 65%) had adverse effects reported in their psychiatric notes. The most common adverse effects were daytime sedation and anger which were reported in two patients each. The majority of patients followed tolerated long-term use, with three patients (27%) discontinuing the medication due to both loss of effectiveness and difficulty tolerating the medication related to either behavioral activation (*n* = 2) or mania (*n* = 1). It is of interest that no patients in this sample reported gastrointestinal side effects, which is the most common reason for early discontinuation of SSRIs [20]. The use of lower dosages of SSRIs and a slower titration schedule are known to mitigate SSRI-related side effects and the dosage titration pattern observed in this study may explain why this was observed.
