Effectiveness and tolerability of eight-week treatment with dosulepin hydrochloride in patients with major depressive disorder not responding to four consecutive weeks of treatment with single selective serotonin reuptake inhibitor

M. Suresh Kumar, Amrit Pattojoshi


Background: Though manageable, major depressive disorder remains an underdiagnosed and undertreated condition. The objective of this study was to assess the effectiveness and safety of 8 weeks of treatment with the tricyclic antidepressant dosulepin hydrochloride in patients with depressive episodes not responsive to 4 consecutive weeks of treatment with a single selective serotonin reuptake inhibitor (SSRI).

Methods: Patients diagnosed with depressive episode without psychotic symptoms (by ICD-10 diagnostic criteria for research), mini-mental state examination score of ≥24, and not responsive to four weeks of treatment with SSRIs (<50% reduction in depressive symptoms) were enrolled. The main outcome measures were mean change in the Hamilton depression, Hamilton anxiety, and insomnia severity index scores at Week 8 compared to baseline. Adverse events were recorded for safety assessment.

Results: A total of 94 patients were enrolled, of which, 90 (95.7%) patients completed the study. Compared to baseline, 8 weeks of treatment significantly changed the HAM-D score by -12.7 (p<0.0001), HAM-A score by -8.3 (p<0.0001), and ISI score by -10.5 (p<0.0001). One patient reported anemia and was withdrawn from the study. Dry mouth and insomnia followed by headache, blurred vision, and drowsiness were the most commonly reported side effects as measured with the antidepressant side-effects checklist. Most side effects were of mild intensity and were related to study medication.

Conclusions: Eight weeks of treatment with dosulepin hydrochloride resulted in significant and clinically relevant improvements in depression, anxiety, and insomnia symptoms in Indian patients with MDD.


Dosulepin, Tricyclic antidepressants, Major depressive disorder, Hamilton depression score, Hamilton anxiety score, Insomnia severity index

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Kraus C, Kadriu B, Lanzenberger R, Zarate CA, Kasper S. Prognosis and improved outcomes in major depression: a review. Transl Psychiatry. 2019;9:127.

Otte C, Gold S, Penninx BW, Pariante CM, Etkin a, Fava M, et al. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065.

Choo C, Diederich J, Song I, Ho R. Cluster analysis reveals risk factors for repeated suicide attempts in a multi-ethnic Asian population. Asian J Psychiatr. 2014;8:38-42.

Large M. Study on suicide risk assessment in mental illness underestimates inpatient suicide risk. BMJ. 2016;532:i267.

Cuijpers P, Smit F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72:227-36.

Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW, Ho RC. Prevalence of depression in the community from 30 Countries between 1994 and 2014. Sci Rep. 2018; 8:2861.

Depression and other common mental disorders: global health estimates. Available at: http://apps., Accessed on 01 February 2021 .

Lecrubier Y. Widespread under recognition and undertreatment of anxiety and mood disorders: results from 3 European studies. J Clin Psychiatry. 2007; 68(2):36-41.

Cleare A, Pariante C, Young A, Anderson I, Christmas D, Cowen P, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2015;29:459-525.

Little A. Treatment-resistant depression. Am Fam Physician. 2009;80:167-72.

Balestri M, Calati R, Souery D, Kautzky A, Kasper S, Montgomery S, et al. Socio-demographic and clinical predictors of treatment resistant depression: a prospective European multicenter study. J Affect Disord. 2016;189:224-32.

Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014; 140:774-815.

Valdivia I, Rossy N. Brief treatment strategies for major depressive disorder: Advice for the primary care clinician. Adv Practice Nurs. 2004;4:1.

Dupuy JM, Ostacher MJ, Huffman J, Perlis RH, Nierenberg AA. A critical review of pharmacotherapy for major depressive disorder. Int J Neuropsychopharmacol. 2011;14:1417-31.

Arroll B, Macgillivray S, Ogston S, Reid I, Sullivan F, Williams B, et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med. 2005;3:449-56.

Williams JW Jr, Mulrow CD, Chiquette E, Noël PH, Aguilar C, Cornell J. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med. 2000;132:743-56.

Magni LR, Purgato M, Gastaldon C, Papola D, Furukawa TA, Cipriani A, et al. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev. 2013;7:CD004185.

Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med. 2005;143:415-26.

Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369-88.

Khan A, Brown WA. Antidepressants versus placebo in major depression: an overview. World Psychiatr. 2015;14:294-300.

de Boer C, Mattace-Raso F, van der Steen J, Pel JJ. Mini-mental state examination subscores indicate visuomotor deficits in Alzheimer's disease patients: A cross-sectional study in a Dutch population. Geriatr Gerontol Int. 2014;14:880-5.

Sallam K, Amr M. The use of the mini-mental state examination and the clock-drawing test for dementia in a tertiary hospital. J Clin Diagn Res. 2013;7:484-8.

Bagby RM, Ryder AG, Schuller DR, Marshall MB. The Hamilton depression rating scale: Has the gold standard become a lead weight? Am J Psychiatr. 2004;161:2163-77.

Thompson E. Hamilton rating scale for anxiety (HAM-A). Occup Med. 2015;65:601.

Morin CM, Belleville G, Bélanger L, Ivers H. The insomnia severity index: Psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep. 2011;34:601-8.

Shahid A, Wilkinson K, Marcu S, Shapiro CM. Insomnia Severity Index (ISI). STOP, THAT and one hundred other sleep scales. New York: Springer; 2011.

Vyas JN, Sharma P, Singhal AK, Agarwal S. A comparative study of dothiepin (prothiaden) and imipramine in depression. Indian J Psychiatr. 1989; 31:151-6.

Smith K. Mental health: a world of depression. Nature. 2014;515:181.

Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J. Changes in the global burden of depression from 1990 to 2017: Findings from the Global Burden of Disease study. J Psychiatr Res. 2020;126:134-40.

Sagar R, Dandona R, Gururaj G, Dhaliwal RS, Singh A, Ferrari A, et al. India state-level disease burden initiative mental disorders collaborators. The burden of mental disorders across the states of India, the global burden of disease study 1990-2017. Lancet Psychiatr. 2020;7:148-61.

Chaturvedi MK, Agarwal PK, Pareek NK, Vyas BK. A comparative evaluation of dothiepin (prothieden) and imipramine. Indian J Psychiatr. 1980;22:124-6.

Welch CP, Tweed JA, Smithers A, Gostick NK, Raniwalla J. A double-blind, comparative study of dothiepin and clomipramine in the treatment of major depressive illness. Int J Clin Pract. 1997;51:360-3.

Mahapatra SN, Hackett D. A double-blind, placebo-controlled comparison of sertraline and dothiepin in the treatment of major depression in general practice. Int J Clin Pract. 1997;51:209-13.

Blacker R, Shanks NJ, Chapman N, Davey A. The drug treatment of depression in general practice: a comparison of nocte administration of trazodone with mianserin, dothiepin and amitriptyline. Psychopharmacol. 1988;95:S18-24.

Beaumont G, Gringras M, Hobbs FD, Drury VW, Freeling P, Tylee A, et al. A randomized, double-blind, multi-centre, parallel-group study comparing the tolerability and efficacy of moclobemide and dothiepin hydrochloride in depressed patients in general practice. Int Clin Psychopharmacol. 1993; 7:159-65.

Dhavale HS, Gawande S, Bhagat V, Durge V, Londhe V, Kini S, et al. Evaluation of efficacy and tolerability of dothiepin hydrochloride in the management of major depression in patients suffering from rheumatoid arthritis. J Indian Med Assoc. 2005; 103:291-4.

Lancaster SG, Gonzalez JP. Dothiepin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs. 1989;38:123-47.

Donovan S, Dearden L, Richardson L. The tolerability of dothiepin: a review of clinical studies between 1963 and 1990 in over 13,000 depressed patients. Prog Neuropsychopharmacol Biol Psychiatr. 1994;18:1143-62.

Zusky P, Manschreck TC, Blanchard C, Rosenbaum J, Elliot C, Lou P. Dothiepin hydrochloride: treatment efficacy and safety. J Clin Psychiatry. 1986;47:504-7.

Handley SA, Flanagan RJ. Drugs and other chemicals involved in fatal poisoning in England and Wales during 2000 - 2011. Clin Toxicol (Phila). 2014;52:1-12.