Given that Duloxetine has been approved for the treatment of MDD, GAD, stress urinary incontinence, diabetic neuropathy and fibromyalgia [3
], the present study agrees with international guidelines (i.e., Canadian Network for Mood and Anxiety Treatments -CANMAT-, World Federation of Societies of Biological Psychiatry –WFSBP-) [28
], except for a subgroup of patients with BD and current major depressive episode. With respect to BD, even though recent studies have reported the induction of hypomania and rapid cyclic in bipolar patients treated with Duloxetine, even in association with other compounds [30
], no manic switch was reported in the present sample. This result should likely be put in relation with the concomitant use of mood-stabilizers and antipsychotic agents in bipolar patients.
With respect to medical comorbidities, Duloxetine should be avoided in patients with a creatinine clearance of <30 mL/min and in patients with hepatic impairment [31
]. Duloxetine has been associated with slight increase in blood pressure but not with clinically significant cardiovascular risks (e.g., increased heart rate or blood pressure) [32
]. Duloxetine is generally considered safe and well tolerated in patients with comorbid diabetes [33
]. Significant increase in body weight has not been generally reported with Duloxetine therapy and a recent study focusing on this aspect observed that Duloxetine-treated patients experienced weight loss after short-term treatment, followed by modest weight gain over longer-term treatment. Taken as a whole, the size of the weight changes observed in the above-mentioned instead of present study and other clinical trials [34
] suggests that this compound is supposed to have minimal effects on weight for most patients.
Given that the majority of patients of the present sample had a medical comorbidity, this study is consistent with literature about Duloxetine’ tolerability and safety in presence of medical illness [35
Mean dosage of Duloxetine was 70 mg/day (± 28.6), which is within the recommended range in order to achieve major efficacy according to international guidelines (60-120 mg/day) [36
]. From this perspective, a recent double-blind randomized trial found no significant differences in terms of efficacy when comparing Duloxetine 60mg/day and 120mg/day in the treatment of severe depressive symptoms [38
]. However, in cases of treatment resistance and/or multiple comorbidity, dosages above 60 mg/day may be required [13
Side effects were reported by 15 % of the sample. Given that all reported symptoms were transient and mild, in the present study Duloxetine showed an overall favourable tolerability. The most frequent side-effects were sedation and gastrointestinal symptoms. From this perspective, the most important result of the present study is that Duloxetine appeared to be well-tolerated also when used in co-administration. In fact, the majority of the sample was taking the compound in polytherapy (68 %). Of note, no differences in terms of tolerability were found when comparing mono- versus polytherapy. If, on one hand, positive tolerability in the polytherapy group might be read in light of a prior attitude to tolerate complex pharmacological regimens, on the other hand, data from the monotherapy group seem to support the specific tolerability of the molecule. Indeed, reported data are consistent with literature about Duloxetine’ tolerability [39
]. Other frequently observed side-effects, such as dry mouth, headache, dizziness and fatigues, were not experienced by our sample [4
Recent studies have shown that Duloxetine is effective and well tolerated also in the elderly, with promising results on cognitive functions [39
]. From this perspective, the present study is consistent with these data, given that approximately 1/4 of the sample could aged between 65 and 85 years and no significant difference was be detected when comparing side effects according to age (< or ≥ 65 years). A recent article on this topic found Duloxetine to be well-tolerated and safe even for the elderly, although indirect comparisons suggested that older people were more likely to experience dry mouth and constipation [40
]. In this specific perspective, however, no difference in terms of type of side-effects was found in the present sample when comparing subjects < 65 years with the elderly.
Given that Duloxetine is primarily metabolized by CYP1A2 and, in light of its moderate capacity to inhibit CYP2D6, caution should be used when co-administered with drugs that inhibit CYP1A2 (e.g.: amitriptyline, clomipramine, clozapine, imipramine) or drugs that are metabolized by CYP2D6 enzymes (e.g.: fluoxetine, paroxetine, venlafaxine, haloperidol, perfenazine, risperidone, tioridazine, desipramine, amitriptyline, clomipramine and nortriptyline) [41
]. In the present study, Duloxetine was mostly used in association with other compounds (68 % of the sample), such as antidepressants, mood stabilizers and atypical antipsychotics and, even though among associated compounds there were some of the aforementioned molecules, no interaction in terms of tolerability was reported. Another appreciable result from the present study is the high rate of benzodiazepines co-administration (60%). Even though benzodiazepines were in most cases administered before Duloxetine, it is noteworthy to mention a recent study which indicated that Duloxetine may enhance the effects of benzodiazepines [42
The present study has some limitations that need to be acknowledged. In particular, the retrospective collection of clinical information might have limited the reliability of some measures. In addition, the frequent administration of Duloxetine within different polytherapy regimens might represent a confounding factor in the evaluation of side effects, so that studies focused on the tolerability of Duloxetine within standardized treatments are required. Moreover, reported results may refer to patients seeking psychiatric treatment and may not be representative of the entire population of subjects affected by comorbid affective disorders. In fact, prospective randomized double-blind studies on this topic with more specific measures of effectiveness are warranted in order to confirm the present results. Finally, given that this was a naturalistic, open study and not a randomized controlled trial, caution should be taken when looking at some positive results.
In conclusion, Duloxetine was well tolerated in a large sample of patients with affective disorders and psychopathological and medical comorbidities, with only minor and transient side-effects both in mono- and polytherapy sub-groups; moreover, it was safely associated with other psychotropic drugs across different groups of age, including the elderly.