Higher-dose weekly fluoxetine in hemodialysis patients: A case series report

Abstract

Objective:

The antidepressant medication fluoxetine at 90mg dosed weekly is as effective and safe as standard formulation fluoxetine 20mg dosed daily in patients with major depressive disorder (MDD). Weekly fluoxetine has not been well-studied in hemodialysis patients, and doses beyond 90mg/week have not been described in this population. This case series, derived from a larger study on depression in hemodialysis patients, describes the use of weekly fluoxetine at dosages beyond 90mg/week.

Method:

Hemodialysis patients with depressive symptom severity scored ≥ 10 on the 9-item Patient Health Questionnaire (PHQ9) and MDD confirmed with Mini International Neuropsychiatric Interview (MINI), were initially prescribed daily fluoxetine for 2 weeks then transitioned to weekly fluoxetine. Dosage titration was made at the discretion of the prescribing clinician. Fluoxetine was continued for a total of 12 weeks.

Results:

4 women, ages 24–65 years, on hemodialysis for 1 to 18 years, were started on weekly fluoxetine that was increased over several weeks up to 180mg. Side effects included restlessness, dry mouth, sedation and lightheadedness. Two patients ultimately had their weekly fluoxetine decreased back to 90mg. However, all 4 continued weekly fluoxetine as part of post-study aftercare and no longer met diagnostic criteria for MDD, current episode.

Conclusions:

Weekly fluoxetine at doses of 180mg may be a reasonable treatment consideration for hemodialysis patients who have partial or insufficient antidepressant response. Side effects may limit tolerance of the 180mg dose in some individuals. Future research should investigate longer-term health outcomes of weekly-fluoxetine in this population.

Introduction:

Approximately 20–30% of hemodialysis patients meet diagnostic criteria for MDD [1–3]. Depression among hemodialysis patients is associated with poor outcomes, including poor engagement in care, inadequate nutrition, hospitalization, and premature death [4–8]. In spite of negative effects of depression on health outcomes, clinicians may be reluctant to prescribe antidepressant medications as dialysis patients take a median of 19 pills per day [9]. To the best of our knowledge, weekly fluoxetine has not been studied in hemodialysis patients and this case series is the first to observe weekly fluoxetine 90–180mg in this population. However, studies in the general population have found that an enteric-coated formulation of the antidepressant medication fluoxetine at a weekly dose of 90 mg is as effective and safe as a standard formulation of fluoxetine at a daily dose of 20 mg in the management of major depression (MDD) [10–12]. Moreover, weekly fluoxetine may be more convenient for patients, is associated with higher rates of adherence, and does not require dose adjustments in kidney failure patients (although multi-dose studies in hemodialysis patients have not been performed) [13–17]. This case series, derived from a larger study on depression treatment in dialysis patients, describes the use of weekly fluoxetine at dosages beyond 90 mg/week.

Methods:

Data for this analysis is derived from a larger ongoing research study investigating the assessment and treatment of hemodialysis patients with depressive symptoms. The larger study is described elsewhere (clinicaltrials.gov identifier NCT03390933) and has 2 key components, comparison of depressive symptoms on different depressive symptom severity rating scales and a prospective treatment phase for individuals with major depressive disorder (MDD). The larger studies’ dosing guidelines were based on a previous study’s work describing transition from daily fluoxetine to weekly fluoxetine using a conversion rate of 20mg daily = 180mg weekly drug [18]. Due to a relatively greater risk of medication side effects in hemodialysis patients, the patients in this case series and the corresponding larger study, are only started on weekly fluoxetine after establishing tolerability with 14 days of daily dosed fluoxetine. Furthermore, the weekly dose of fluoxetine is only increased above 90mg in those who present with partial response but continue to have clinically distressful depressive symptoms and who have no significant side effects.

The MDD diagnosis is confirmed with the Mini International Neuropsychiatric Interview (MINI) [19] and clinical assessment by a mental health nurse practitioner. Individuals with MDD, who have depressive symptom severity scored ≥ 10 on the 9-item Patient Health Questionnaire (PHQ9) and who do not have contra-indications to fluoxetine are prescribed daily dose fluoxetine 20mg for 14 days to establish drug tolerance then begun on directly-observed therapy (DOT) once weekly. Total study treatment duration with fluoxetine is 12 weeks. Clinical assessment visits, including PHQ9 evaluation are done at baseline and day 3, 1-week and 2-weeks follow-up. Individuals who appear to tolerate daily fluoxetine are then switched to weekly fluoxetine 90 mg/day. Subsequent clinical visits and depression severity assessment is conducted every 2 weeks for a total of 10 weeks, with medication increase up to 180mg once weekly for partial responders permitted at the discretion of the prescribing clinician. The MINI is repeated at the conclusion of the study to confirm clinical response to treatment. At the time of this writing, 15 patients have completed treatment with weekly fluoxetine as part of the larger study. This report describes a sample of these hemodialysis patients prescribed weekly fluoxetine at doses beyond the standard 90 mg dosage.

Depressive symptom severity:

Depressive symptom severity was assessed using the PHQ9 a widely used and validated self-rated depression scale [20]. The PHQ9 is commonly used in primary care settings to both screen for and monitor progress in management of depression. The PHQ9 incorporates diagnostic and statistical manual (DSM) diagnostic criteria, with scores ranging from 0–27. Higher scores indicate worse depressive symptom severity. A score of ≥ 10 is an established threshold for clinically relevant depressive symptoms that are at least moderate in severity. In a previous study in dialysis patients [10], a PHQ9 ≥ 10 had a sensitivity of 92% and a specificity of 92% for depressive disorder. It is important to note that although depressive symptom severity plays an important clinical role in screening and monitoring progress of depression treatment, it is not a diagnostic tool. This becomes especially important to consider in patients on hemodialysis due to the overlap of symptoms of depression (e.g. appetite change, sleep disturbance, low energy) and symptoms of persistent metabolic derangements in hemodialysis patients (e.g. nausea, nocturnal cramps, feeling washed out after treatment) [21]. Therefore, diagnosis of MDD in patients with baseline PHQ9 scores of ≥ 10 were confirmed by MINI and clinical assessment by the mental health nurse practitioner.

Drug-related side effects:

Adverse effects from fluoxetine daily and weekly formulations were assessed using clinical interview and observation at follow-up visits by the prescribing clinician.

Case 1:

Ms. A., a 53-year-old female on hemodialysis for the past year, had a baseline PHQ9 of 14. However, Ms. A reported a PHQ9 score of 24 within the first week of treatment in addition to reports of increased symptomatology. This seemingly rapid change in clinical presentation appeared related to an increased comfort in discussing chronic mental health issues with her clinician rather than an increase in experienced depressive symptoms. Thus, we believe that Ms. A’s baseline PHQ9 score of 14 may have been an under-report of her experienced depressive symptomatology. Per chart review, comorbid conditions included Type 2 diabetes with diabetic retinopathy, congestive heart failure, anemia, and history of hypertension. Ms. A. revealed that she had chronic thoughts of suicide since her diagnosis with kidney disease one year prior but denied current suicidal ideation and was able to identify an appropriate plan for safety. At 2 week follow up, Ms. A denied suicidal ideation and felt her mood was improved. Per study protocol, she was started on weekly fluoxetine 90mg one week after completing daily dosing. A week later, week 4 of fluoxetine treatment (PHQ9 was 17), Ms. A. reported increased depressive symptoms, “I’ve been slipping back [into depression] again” but continued to deny suicidal ideation. Her weekly fluoxetine dose was increased to 180mg based on the mental health nurse practitioner’s clinical judgment and the protocol of the larger study for the direct observation of once weekly fluoxetine. One week after increasing the weekly dose, Ms. A reported less anxiety, isolation, improved appetite, and that she had started cooking again. She also denied all suicidal ideation or thoughts of death. No side effects were observed or reported with fluoxetine treatment. Nine weeks after starting fluoxetine, Ms. A was “happier” and denied depressed mood or anhedonia. Twelve weeks after starting fluoxetine (end of study), Ms. A’s PHQ9 was 12 and she continued to deny suicidal ideation. Ms. A continued to report somatic symptoms related to her comorbid physical health conditions which may be reflected in her moderately high PHQ9 score. When the MINI was completed, Ms. A no longer met criteria for MDD current episode as she only had 4 symptoms when 5 are needed for a diagnosis to be made. Her aftercare included biweekly counseling sessions and continuing on weekly fluoxetine 180mg for continuing management of recurrent MDD.

Case 2:

Ms. B, a 65-year-old female on hemodialysis for 1 year, had a baseline PHQ9 score of 15. Comorbid conditions included chronic obstructive pulmonary disease, Type 1 diabetes mellitus, congestive heart failure, hyperparathyroidism, anemia, and arthritis. After taking daily fluoxetine for 2 weeks, Ms. B reported sleeping better and doing more around the house. She was then transitioned to weekly fluoxetine 90mg. At week four of fluoxetine treatment (end of week one of once weekly treatment), Ms. B’s PHQ9 score was 5. One week later, Ms. B. reported feeling the medication wearing off about half way through the week with a return of depressive symptoms. The weekly fluoxetine dose was increased to 180mg per study protocol and prescribing clinician judgement. A week later, Ms. B. was feeling much better. Other than mild stomach upset starting and resolving within 24 hours of the first weekly dose, no side effects were observed or reported. Twelve weeks after starting fluoxetine her PHQ9 was 3 and she no longer met criteria for MDD based on MINI assessment. Aftercare included counseling and follow-up with her primary care provider to continue weekly fluoxetine 180mg.

Case 3:

Ms. C, a 40-year-old female on hemodialysis for 18 years, had a baseline PHQ9 of 17. Comorbid conditions included sleep apnea, congestive heart failure, diabetes, and chronic obstructive pulmonary disease. One week after starting daily fluoxetine 20mg, Ms. C endorsed improved sleep and appetite. She reported mild side effects of nausea and headache for which it was recommended she take the medication with food and take a pain reliever. Side effects resolved and Ms. C was transitioned to weekly fluoxetine 90mg. One week later (week 4 of treatment), her PHQ9 score was 9. Three weeks after starting weekly fluoxetine, Ms. C. reported a fair response to depression and anxiety but by the end of the week she noticed increased restlessness, “cotton mouth,” and sedation. As side effects were tolerable and depression was still burdensome, Ms. C’s weekly fluoxetine dose was increased to 180mg. One week after starting the increased fluoxetine dose, Ms. C reported that medication benefits for mood lasted the entire week and she denied any side effects. However, Ms. C. was having difficulty managing dietary adherence and she required more frequent hemodialysis sessions. Two weeks later, although she continued to report a decrease in depressed mood and anhedonia, Ms. C’s PHQ9 score had more than doubled, primarily attributable to physical health complaints. She also reported dry mouth, sedation, and restless legs despite not having experienced these side effects while on the once daily 20mg dose. Ms. C.’s engagement in physical self-care continued to be sub-optimal with deterioration in fluid overload, bilateral ear infections, and difficulty breathing. Eleven weeks after starting fluoxetine, Ms. C. requested to decrease weekly fluoxetine dose back to 90mg, which she remained on for the duration of the study. Her final PHQ9 score was 13 and her feelings of restlessness had resolved since reducing her fluoxetine dose to 90mg once weekly. She denied any other side effects. Ms. C no longer met criteria for MDD and her aftercare included continuing weekly fluoxetine 90 mg. At the end of the study, Ms. C no longer reported depressed mood or anhedonia. One or both symptoms are required for a diagnosis of major depressive episode to be made. Therefore, despite Ms. C’s PHQ9 score corresponding with moderate depression based on typical scoring of this scale, it was concluded that Ms. C’s PHQ9 score was falsely elevated by her suboptimal physical health condition and determination of remission was made by clinical assessment and MINI.

Case 4:

Ms. D., a 24-year-old female on hemodialysis for 7 years, had a baseline PHQ9 of 12. Comorbid conditions included morbid obesity, metabolic syndrome, Type 2 diabetes mellitus, hyperparathyroidism, and anemia. She had recently discontinued use of marijuana. Three days after initiation of daily fluoxetine 20mg, Ms. D. had more energy but reported mild nausea that improved when taking her dose with food. By week 1 follow-up, Ms. D’s nausea had resolved, however, she reported some itchiness that started when she began fluoxetine one week ago. By the end of the second week of daily fluoxetine, Ms. D denied almost all symptoms of depression and reported only several days of depressed mood in the past 2 weeks. She was transitioned to weekly fluoxetine 90mg. A week later (week 4 of treatment), Ms. D.’s PHQ9 score was 15; additionally, she reported a new-onset episode of thoughts of self-harm, although she denied suicidal ideation. However, Ms. D. reported that her mood would improve for the first part of the week after taking weekly fluoxetine, but she noticed worsening depression and lethargy a few days before her next scheduled dose. Fluoxetine was increased to 180 mg weekly. A week later Ms. D. reported increase in lightheadedness. It was not clear if the lightheadedness was due to fluoxetine or changes in fluid load (Ms. D. had been gaining 5–6 kg between dialysis sessions and now was gaining 2–3kg). Additionally, Ms. D’s dialysis nurse noted that Ms. D. had intermittent episodes of lightheadedness and syncope predating fluoxetine treatment. At 10 weeks after fluoxetine initiation, Ms. D no longer endorsed depressed mood or anhedonia but she requested a decrease in the dose of fluoxetine to 90mg due to ongoing lightheadedness which she attributed to fluoxetine. Her final 12-week PHQ9 was 5 and she no longer met criteria for MDD by MINI assessment denying both depressed mood and anhedonia. While initially ambivalent about continuing weekly fluoxetine, eventually Ms. D. elected to continue treatment with 90 mg as part of aftercare. Mental Health services were also recommended. It is important to note that Ms. D showed type B personality disorder traits (no diagnosis of personality disorder was attempted in the course of this study) and was newly sober from marijuana at the start of the medication trial. These factors may have affected Ms. D’s response to treatment and treatment outcomes. However, based on clinical assessment by the mental health nurse practitioner, Ms. D was able to make informed decisions about her continued mental health treatment after receiving proper psychoeducation about her conditions.

Discussion:

This case series of 4 hemodialysis patients with MDD, describes directly- observed treatment with weekly fluoxetine at dosages of 90–180 mg/week. The four patients are a subset of those treated with weekly fluoxetine (N=15) as part of a larger study examining the safety and efficacy of directly observed, once weekly fluoxetine in patients on hemodialysis. Side effects included restlessness, dry mouth, sedation and lightheadedness. Two patients ultimately had their weekly fluoxetine decreased from 180mg back to 90 mg, however all 4 patients continued on weekly fluoxetine as part of post-study aftercare and all gained remission from MDD based on structured diagnostic interview (MINI).

Despite the small sample and short timeframe of the study, the findings are important on several fronts. To the best of our knowledge, there are no other published reports on use of weekly fluoxetine beyond 90 mg in hemodialysis patients and clinicians who treat these individuals have a limited evidence base to guide management for symptoms of depression/MDD. Additionally, fluoxetine weekly is not widely used in clinical settings and this report identifies a potential clinical situation where this drug formulation could optimize care engagement and outcomes.

Fluoxetine and its desmethyl metabolite, norfluoxetine, are selective inhibitors of serotonin uptake [22]. This specificity may explain fluoxetine’s relative absence of anticholinergic, hypotensive and cardio-depressant side effects [23]. Aronoff and colleagues [23] examined the effects of decreased renal function on the disposition and elimination of oral fluoxetine 40mg on 25 adult men. Blood levels of fluoxetine and norfluoxetine were measured sequentially in the 48 hours after drug initiation and then 3x/week for 4 weeks. Urine was also assayed for fluoxetine and norfluoxetine. Both fluoxetine and norfluoxetine were eliminated slowly and there were no correlations between renal dysfunction and drug disposition or elimination. Additionally, plasma concentrations of fluoxetine and its metabolite were not significantly changed by hemodialysis. The pharmacokinetic properties of fluoxetine thus appear to be favorable for use in patients with severe renal impairment. There is the possibility of gender differences in fluoxetine metabolism [24]; However, our findings of relatively good tolerability of weekly fluoxetine at relatively high doses in a sample of all women are in-line with previous kinetic studies.

Weekly fluoxetine was approved by the FDA for individuals with MDD nearly 2 decades ago [25]. Studies suggested that relapse rates were similar between individuals with MDD continued on daily dosing vs. those that were switched to weekly fluoxetine [12, 26]. Studies of weekly fluoxetine conducted in general MDD sample suggest that side effects of weekly drug are similar to the daily/immediate release formulation [26]. Most common side effects with weekly fluoxetine in general MDD samples are nervousness, headache, asthenia and diarrhea. Two individuals in our sample had nausea when initially started on oral fluoxetine. Both had nausea resolve when fluoxetine was taken with food. Headache, which resolved with use of pain reliever, was reported by one patient in our sample upon initiation of daily fluoxetine. Nervousness or restlessness was observed in one individual on 180 mg of weekly drug, which resolved on dosage reduction.

A small study of 39 outpatients with MDD described transitioning from oral fluoxetine (dosage of 10–80 mg/day) to weekly fluoxetine at dosages of 90–540 mg [18]. The majority of individuals in this sample (29/39, 74%) took fluoxetine weekly at a dosage of 180 mg or more. Seven out of the sample (7/39, 18%) started weekly fluoxetine without an oral drug lead-in. For those on oral fluoxetine who were transitioned to weekly drug, weekly dosage was determined based on a conversion of 20 mg oral drug= 180 mg weekly drug. Comorbid medical diagnoses included chronic headaches, chronic pain, fibromyalgia, status-post cerebral vascular accident, closed head injury, temporal lobe epilepsy, recovering alcoholism and vascular dementia. On weekly fluoxetine, in the report by Buongiorno [18], there were no new spontaneous reports of nervousness, asthenia, diarrhea, abnormal thinking or somnolence and no serious adverse events or hospitalizations occurred. In our hemodialysis sample we took a more cautious approach and uniformly started with oral fluoxetine and only increased above 90 mg of weekly fluoxetine in those who appeared to have continuing depressive symptoms and without significant side effects. Given the relatively greater risk of medication side effects in hemodialysis patients this incremental approach may optimize benefit vs. risk burden.

A key feature of weekly fluoxetine is the potential to improve medication adherence, which is generally better compared to daily fluoxetine [11, 26]. Patients on hemodialysis have a host of behaviors that they need to implement and sustain, including taking medications, keeping dialysis and other medical appointments as well as diet and other self-care directions. High pill burden and complexity of medication regimens, frequently a problem for hemodialysis patients, are frequently cited as barriers to medication adherence in this population (12.5–98.6% nonadherence prevalence in hemodialysis population depending on definition for nonadherence used) [27–29]. However, patients typically attend dialysis treatment three times weekly which allows for directly-observed medication administration, potentially increasing adherence to prescribed weekly medications. Depression also has negative effects on the ability of people with chronic conditions to manage their own health. Better adherence by lowering pill burden and medication dosing complexity with the use of once weekly, directly observed antidepressant medication may help sustain healthy behaviors for individuals that are vulnerable to physical health deterioration related to their severe renal disease [13]. Additionally, our findings from this case series suggest that ongoing depressive symptoms in individuals who are on weekly fluoxetine 90 mg could potentially benefit from a dosage increase to 180 mg.

It remains unclear why these 4 patients, out of the 15 treated with fluoxetine in the larger study, required the 180mg weekly dose. However, based on the patient’s reports of the medication seeming to wear off half way through the week, the answer may lie in individual differences in medication metabolism, with higher metabolizers needing higher doses. Once our patients started the increased weekly dose, they reported the antidepressant effect lasting the entire week. Further research with larger sample sizes are needed to explore the pharmacokinetic reasons for differential medication response.

In conclusion, weekly fluoxetine at doses of 180 mg may be a reasonable treatment consideration for hemodialysis patients who have partial and/or insufficient antidepressant response on weekly fluoxetine 90 mg. Side effects may limit tolerance of the 180 mg dose in some individuals. Future research should investigate longer-term effects of weekly-fluoxetine on health outcomes in hemodialysis patients with depression.