Treatment-resistant obsessive-compulsive disorder (TR-OCD) is defined as a disorder that shows no improvement despite the use of adequate cognitive-behavioral therapy (CBT) and at least two different selective serotonin reuptake inhibitors (SSRIs or clomipramine) in maximum-tolerated doses for at least 10 weeks.1 Although effective and safe treatments are available for pediatric OCD, longitudinal studies have reported that 41% of pediatric OCD cases are persistent and 33% of cases are moderate or severe OCD.2 More recent data suggest the use of neuroleptics, deep-brain stimulation, and neurosurgical ablation are effective for TR-OCD.3
Venlafaxine was demonstrated to be effective in some TR-OCD patients with a low response to SSRIs.4 Although studies on the use of mirtazapine are insufficient, there are some reports that mirtazapine may be effective in the treatment of OCD.5,6
Venlafaxine is associated with an increased risk of adverse effects in adolescents and its use is rare,7 but in the patient discussed in this report, the effective and safe use of venlafaxine, mirtazapine, and aripiprazole in combination in an adolescent with TR-OCD is discussed. At the time of this writing, this is the first reported case in which venlafaxine, mirtazapine, and aripiprazole are used in combination in an adolescent with TR-OCD.
The patient was a 14-year-old girl. Her symptoms began 3 years prior. In her first psychiatric consultation with the authors, she stated that she washed her hands 30 to 40 times per day and bathed twice a day for approximately 1.5 to 2 hours. She never used the belongings of others (eg, plates, cutlery, towels). She could not use the toilets at school, and tried not to touch anything in school or only touched things with a napkin. She wanted her mobile phone to be 100% charged at all times; if it was only 99% charged then she felt uneasy and would try to charge it. She checked her school assignments three times to make sure they were properly completed. Her friends teased her about her obsessions, which would make her upset, and she would have crying episodes at home and school.
The first time we saw the patient, she cried and said that she had been receiving treatment for years but her problems were not getting any better, and she now thought that the only way to eliminate this disease was to die. These depressive thoughts were associated with the idea that her OCD would not improve and that she did not want to live with this disease any longer. Her Depression Inventory scale score was 36 points (cut off: 19), State Trait Anxiety Inventory (STAI)-1 scale score was 50, and STAI-2 scale score was 52 points (cut off: 40). Her Clinical Global Impression scale (CGI-S) was 6, and her Children's Yale-Brown Obsessive Compulsive Scale (CY-BCOS) score was 34. TR-OCD and depression diagnoses were established. It was thought that her depression had developed secondary to OCD.
Although she had tried various treatments over the past 3 years, she had not obtained any benefits from them. She had been unable to benefit from CBT due to intense anxiety. It was learned that sertraline (200 mg/day), fluoxetine (60 mg/day), risperidone (2 mg/day), aripiprazole (15 mg/day), and clomipramine (75 mg/day) had been used at different times. She had been trying different treatments for 3 years. When she presented to our clinic, her treatment regime was fluoxetine (60 mg/day), aripiprazole (15 mg/day), and clomipramine (75 mg/day). She did not use clomipramine regularly due to experiencing a dry mouth, dizziness, and hypotension, but she had used the other drugs regularly for 6 months.
Venlafaxine was started at a dose of 37.5 mg/day and increased to a dose of 75 mg/day and then to 150 mg/day at 1-week intervals. The patient was initially given 150 mg/day of venlafaxine for 12 weeks, and then aripiprazole at a dose of 20 mg/day was added for the augmentation of TR-OCD and fluoxetine was also stopped. After 12 weeks of follow-up, her CGI-I score was 3 and CY-BCOS score was 29.
Mirtazapine (15 mg) was started, and the dose was increased to 30 mg/day 1 week later. In her last assessment, she had fewer complaints and she seemed happier due to an improvement in her OCD. Her CGI-I score was 2, and her CY-BCOS score was 20 (Table 1). There were no adverse effects seen with this combined treatment. The patient was observed for 8 months with the current treatment, and her well-being was maintained.
Treatment Regimens by Week
In this case, venlafaxine and mirtazapine were used based on the data of success in adult patients, as there was no information on the use of these medications for children or adolescents with OCD who had not benefited from standard treatment.
In a randomized study of adults comparing paroxetine (60 mg/day) and venlafaxine (300 mg/day), there was no difference in the treatment response.8 When clomipramine (150–225 mg/day) and venlafaxine (225–350 mg/day) were compared, venlafaxine was shown to be as effective as clomipramine, and no significant difference was found in terms of efficacy.9 Venlafaxine has been reported to have fewer side effects and better tolerability than clomipramine.9 In one study, venlafaxine was reported to be effective in the treatment of OCD that was resistant in prior SSRI treatment trials in 22 of 29 patients.10 Although data in adults are not consistent in OCD cases, this finding is promising.
The low incidence of adverse effects, the early onset of activity compared with other medication groups, and observations from adults led to the suggestion that venlafaxine could be effective in children and adolescents. A limited number of studies provide information on the use of venlafaxine in children and adolescents with depression, attention-deficit/hyperactivity disorder, and autism.11,12
In this patient, the venlafaxine dose was titrated, and the patient tolerated and partially benefited from the treatment. Subsequently, the aripiprazole dose was increased to 20 mg/day to fortify the treatment effect. In studies of adult patients with TR-OCD, antipsychotics and glutamatergic agents have been effective.3,13 In both children and adults, the efficacy of aripiprazole augmentation in TR-OCD has been demonstrated in nonrandomized studies.14,15 In this patient, as an adequate response was not obtained in spite of aripiprazole augmentation, mirtazapine (30 mg/day) was added to the treatment to increase the serotonergic and noradrenergic effects.
The combination of venlafaxine and mirtazapine increases the risk of serotonergic syndrome, the combination of venlafaxine and aripiprazole increase the level of aripiprazole through CY2D6 metabolism, and the combination of mirtazapine and aripiprazole may increase the risk of sedation. None of these possible adverse effects were observed in this case.
Mirtazapine, an antidepressant agent characterized by noradrenergic and 5-HT receptor antagonism that indirectly enhances serotonin neurotransmission, has not been sufficiently studied in OCD, but there is preliminary evidence of the efficacy of mirtazapine as an anti-OCD drug either in monotherapy or as an adjunctive agent.16 The efficacy of mirtazapine alone in adult patients with TR-OCD has been shown in at least one study.16 In a single-blind, randomized controlled study, it was found that the addition of mirtazapine to OCD patients receiving SSRI therapy provided faster recovery of OCD symptoms but did not change response rates.17
The combination of venlafaxine and mirtazapine is effective for treating depressive disorders that are difficult to treat by increasing serotonergic and noradrenergic transmission.18 This case shows that a combination of venlafaxine, mirtazapine, and aripiprazole can be safe and effective in an adolescent with TR-OCD. The effect of venlafaxine and mirtazapine on both presynaptic and postsynaptic serotonergic transmission may explain the usefulness of this combination in TR-OCD.
In the context of this case, it is difficult to understand whether antidepressant agents used in treatment decreased OCD symptoms by improving depression or exerted a direct anti-obsessional effect. As can be understood from the patient history, depression developed secondary to OCD. We postulate that depression treatment cannot be expected to improve OCD symptoms to this extent on its own, so there must be a strong anti-obsessional effect as well.
To the best of our knowledge, this is the first report of an adolescent patient with TR-OCD who responded favorably to a combination of a serotonin-norepinephrine reuptake inhibitor (venlafaxine), an alpha-2 adrenergic receptor antagonist (mirtazapine), and an atypical antipsychotic (aripiprazole). The combination of venlafaxine and mirtazapine is rare in adolescents, but this case shows that it can be used as a safe and effective alternative in children with OCD who cannot obtain benefits from other therapies.
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- Balachander S, Kodancha PG, Arumugham SS, Sekharan JT, Narayanaswamy JC, Reddy YCJ. Effectiveness of venlafaxine in selective serotonin reuptake inhibitor-resistant obsessive-compulsive disorder: experience from a specialty clinic in india. J Clin Psychopharmacol. 2019;39(1):82–85. doi:10.1097/JCP.0000000000000989 [CrossRef] PMID:30516575
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- Xu Y, Bai SJ, Lan XH, Qin B, Huang T, Xie P. Randomized controlled trials of serotonin-norepinephrine reuptake inhibitor in treating major depressive disorder in children and adolescents: a meta-analysis of efficacy and acceptability. Braz J Med Biol Res. 2016;49(6):S0100-879X2016000600704. doi:10.1590/1414-431x20164806 [CrossRef] PMID:27240293
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Treatment Regimens by Week