Investigation of the efficiency of various antidepressant replacement regimens in the development of SSRI-induced apathy syndrome

Selective serotonin reuptake inhibitors (SSRI)-induced apathy syndrome occurs in 5–20% of patients taking these drugs.

Objective: to investigate the possibility and advantages of switching patients with SSRI-induced apathy to treatment with a SSRI and norepinephrine reuptake inhibitor.

Patients and methods. The investigation enrolled 105 depressive patients without psychotic symptoms, who were observed to develop symptoms of SSRI-induced apathy during SSRI antidepressant monotherapy for at least 6 months. The patients were randomized to groups: 1) 35 patients were switched to milnacipran (Ixel 50–100 mg/day) with simultaneous antidepressant replacement; 2) 35 patients were prescribed milnacipran with a 2-week gradual discontinuation of the previous SSRI; 3) 35 patients were switched to combined therapy with milnacipran 50–100 mg/day and sulpiride (Eglonyl 50 mg/day). The latter was prescribed to test the hypothesis for the benefits of combined correction of SSRI-induced apathy syndrome. The duration of the investigation was 3 months. Changes in the condition of the patients were assessed during their visits before and 1, 2, 4, 8, and 12 weeks after changing therapy. The efficiency of antidepressant therapy was studied using the 21-item Hamilton Depression Rating Scale (HDRS-21) and the Clinical Global Impression (CGI) rating scale; the changes in the severity of asthenic manifestations were examined according to a subjective asthenia assessment (Multidimensional Fatigue Inventory (MFI-20)). The UKU side effect rating scale was used to verify side effects.

Results and discussion. A significant (p<0.05) pronounced thymoleptic effect of various treatment regimens (simultaneous and gradual replacement with monnacipran monotherapy, as well as a milnacipran-sulpiride combination) was confirmed at week 4 of treatment. There was a reduction in SSRI-induced apathy syndrome when switching to treatment with milnacipran or milnacipran-sulpiride in 71.4–80% of patients. Different therapy replacement regimens showed varying changes in the reduction of heterogeneous asthenoapathic symptoms. A favorable safety profile was established for both monotherapy with milnacipran and its combination with sulpiride.

Conclusion. The antidepressant milnacipran (up to 100 mg/day) exhibits a high efficacy and a good tolerance in case of SSRI-induced apathy syndrome, as well as by a pronounced thymoleptic effect, including when combined with the antipsychotic sulpiride (50 mg/day).

1. Petrova NN, Markin AV. Apathy syndrome in depressed patients treated with selective serotonin reuptake inhibitors. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2020;120(1): 111-7. (In Russ.).

2. Barnhart WJ, Makela EH, Lotocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract. 2004 May;10(3):196-9. doi: 10.1097/00131746-200405000-00010

3. Garland EJ, Baerg EA. Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents. J Child Adolesc Psychopharmacol. 2001 Summer; 11(2):181-6. doi: 10.1089/104454601750284090

4. Goodwin GM, Price J, De Bodinat C, Laredo J. Emotional blunting with antidepressant treatments: A survey among depressed patients. J Affect Disord. 2017 Oct 15;221:31-35. doi: 10.1016/j.jad.2017.05.048. Epub 2017 Jun 6.

5. Kim HG, Koo BH, Lee SW, Cheon EJ. Apathy syndrome in a patient previously treated with selective serotonin reuptake inhibitors for depression. Yeungnam Univ J Med. 2019 Sep; 36(3):249-253. doi: 10.12701/yujm.2019.00150. Epub 2019 Mar 15.

6. Opbroek A, Delgado PL, Laukes C, et al. Emotional blunting associated with SSRIinduced sexual dysfunction. Do SSRIs inhibit emotional responses? Int J Neuropsychopharmacol. 2002 Jun;5(2):147-51. doi: 10.1017/S1461145702002870.

7. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study. Br J Psychiatry. 2009 Sep; 195(3):211-7. doi: 10.1192/bjp.bp.108.051110.

8. Price J, Goodwin G. Emotional blunting or reduced reactivity following remission of major depression. Medicographia. 2009;31:152-6.

9. Reinblatt SP, Riddle MA. Selective serotonin reuptake inhibitor- induced apathy: a pediatric case series. J Child Adolesc Psychopharmacol. 2006 Feb-Apr;16(1-2):227-33. doi: 10.1089/cap.2006.16.227

10. Sansone RA, Sansone LA. Bupropioninduced neck and shoulder pain. Pharmacopsychiatry. 2009 Sep;42(5):203-4. doi: 10.1055/s-0029-1220934. Epub 2009 Sep 1.

11. Wongpakaran N, van Reekum R, Wongpakaran T, Clarke D. Selective serotonin reuptake inhibitor use associates with apathy among depressed elderly: a case-control study. Ann Gen Psychiatry. 2007 Feb 21;6:7.

12. Bolling MY, Kohlenberg RJ. Reasons for quitting serotonin reuptake inhibitor therapy: paradoxical psychological side effects and patients satisfaction. Psychother Psychosom. 2004 Nov-Dec;73(6):380-5.

13. Chernova EV, Kozhechkina OV, Ter-Israelyan AYu, Medvedev VE. Efficacy and tolerability of agomelatin (valdoxan) in the treatment of endogenous depression in a day hospital. Zhurnal nevrologii i psikhiatrii im. S.S.Korsakova. 2016; 116(10):43-6. (In Russ.).

14. Sato S. Reconsidering the term 'disinhibition' in selective serotonin reuptake inhibitorsinduced apathy syndrome. Psychiatry Clin Neurosci. 2018 Aug;72(8):624. doi: 10.1111/pcn.12678.

15. Hoehn-Seric R, Lipsey JR, Mcleod DR. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol. 1990 Oct;10(5):343-5.

16. McCabe C, Mishor Z, Cowen PJ, Harmer CJ. Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment. Biol Psychiatry. 2010 Mar 1;67(5):439-45. doi: 10.1016/j.biopsych.2009.11.001. Epub 2009 Dec 24.

17. Medvedev VE. Effectiveness and tolerability of modern antidepressants : results of network meta-analyses and Russian experience. Zhurnal Nevrologii i psikhiatrii im. S.S. Korsakova. 2018; 118(11):109-17. (In Russ.).

18. Medvedev VE. Dysmorphic disorders: clinical and nosological heterogeneity. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2016;8(1): 49-55. (In Russ.). doi: 10.14412/2074-2711-2016-1-49-55

19. Briley M. Improvement of social adaptation in depression with serotonin and norepinephrine reuptake inhibitors. Neuropsychiatr Dis Treat. 2010 Oct 5;6:647-55. doi: 10.2147/NDT.S13171.

20. Dobrushina OR, Medvedev VE. Combined therapy of neurasthenia in general medical practice. Consilium Medicum. 2016;18(2):95-9. (In Russ.).

21. Kardashyan RA, Dobrushina OR, Medvedev VE. Relieving symptoms of neurasthenia in general medical practice. Lechashchii vrach. 2015;(12): 63-7. (In Russ.).

22. Medvedev VE. Differentiated approach in depression therapy. Psikhicheskoe zdorov'e. 2015;(3):45-53. (In Russ.).

23. Medvedev VE. New opportunities for treatment of asthenic disorders in psychiatric, neurological and somatic practice. Psikhiatriya i psikhofarmakoterapiya. 2013;(4):53-9. (In Russ.).

24. Bisserbe JC. Clinical utility of milnacipran in comparison with other antidepressants. Int Clin Psychopharmacol. 2002 Jun;17 Suppl 1: S43-50. doi: 10.1097/00004850-200206001-00006

25. Medvedev VE, Korovyakova EA, Frolova VI, Gushanskaya EV. Antidepressant therapy in patients with cardiovascular diseases. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2019;11(1):131–40. (In Russ.). doi: 10.14412/2074-2711-2019-1-131-140

26. Medvedev VE, Frolova VI, Ter-Israelyan AYu, et al. Therapy of depressive disorders that occur with circannual rhythms. Psikhiatriya i psikhofarmakoterapiya. 2018;20(5):38-43. (In Russ.).

27. Baldwin D, Moreno RA, Briley M. Resolution of sexual dysfunction during acute treatment of major depression with milnacipran. Hum Psychopharmacol. 2008 Aug; 23(6):527-32. doi: 10.1002/hup.955.

28. Chang TT, Leng CH, Wu JY, et al. Lower side effects of milnacipran than paroxetine in the treatment of major depression disorder among Han Chinese in Taiwan. Chin J Physiol. 2008 Dec 31;51(6):387-93.

29. Puozzo C, Hermann P, Chassard D. Lack of pharmacokinetic interaction when switching from fluoxetine to milnacipran. Int Clin Psychopharmacol. 2006 May;21(3):153-8.

30. Sechter D, Vandel P, Weiller E, et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord. 2004 Dec;83(2-3):233-6. doi: 10.1016/j.jad.2004.07.002

31. Medvedev VE. Depressive disorders. In: Martynov AI, editor. Sovremennoe rukovodstvo dlya praktikuyushchikh vrachei [Modern guide for medical practitioners]. Vol. 6. Moscow: Bionika Media; 2018. P. 57-69.

32. Medvedev VE, Dobrovol'skii AV, Trosnova AP. Research of effectiveness and tolerability of Ixel in the treatment of depressive disorders in patients of cardiological hospital. Psikhicheskie rasstroistva v obshchei meditsine. 2007;(4):37-40. (In Russ.).

33. Medvedev VE. Milnacipran (Ixel) in psychiatry and general medicine. Psikhiatriya i psikhofarmakoterapiya. 2016; (2):18-25. (In Russ.).

34. Medvedev VE, Ter-Israelyan AYu, Frolova VI, et al. Experience of use of valdoxan in depression, occurring with cognitive disorders. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2018; 118(2):77-80. (In Russ.).

35. Rouillon F, Berdeaux G, Bisserbe JC, et al. Prevention of recurrent depressive episodes with milnacipran : consequences on quality of life. J Affect Disord. 2000 Jun;58(3):171-80. doi: 10.1016/s0165-0327(99)00109-3