Ten years of maintenance treatment of severe melancholic depression in an adult woman including discontinuation experiences

Abstract

Background There are only few publications on long-term treatments for major depressive disorder (MDD) lasting 5 years or longer. Most clinical controlled trials lasted no longer than 2 years and some recent studies suggested an advantage of cognitive behavioral therapy (CBT) over antidepressants in relapse prevention of MDD.

Methods Exclusively outpatient "real world" treatment of severe melancholia, prospectively documented over 10 years with different serial treatment strategies, discontinuation phenomena and complications.

Methods Compared to CBT, agomelatine, mirtazapine, bupropion and high-dose milnacipran, high-dose venlafaxine (extended-release form, XR) was effective, even sustainably. Asymptomatic premature ventricular contractions (PVCs) were found at the beginning of the treatment of the MDD, which initially led to the discontinuation of high-dose venlafaxine (300 mg daily). Even the various treatment strategies mentioned above were unable to compensate for or prevent the subsequent severe deterioration in MDD (2 rebounds, 1 recurrence). Only the renewed use of high-dose venlafaxine was successful. PVC no longer occurred and the treatment was also well tolerated over the years, with venlafaxine serum levels at times exceeding 5 times the recommended upper therapeutic reference level (known bupropion-venlafaxine interaction, otherwise 2.5 to 3-fold increase with high-dose venlafaxine alone). During dose reduction or after gradual discontinuation of high-dose venlafaxine, rather mild withdrawal symptoms occurred, but as described above, also two severe rebounds and one severe recurrence happened.

Discussion This long-term observation supports critical reflections on the discontinuation of successful long-term treatment with antidepressants in severe MDD, even if it should be under "the protection" of CBT. The PVC seemed to be more related to the duration of the severe major depressive episode than to the venlafaxine treatment itself. A particular prospective observation of this longitudinal case study is that relapses (in the sense of rebounds) during or after previous venlafaxine tapering seemed to herald the recurrence after complete recovery. Remarkably, neither relapses nor recurrence could be prevented by CBT.

Conclusion In this case, high-dose venlafaxine has a particular relapse-preventive (and "recurrence-preventive") effect with good long-term tolerability.

Zusammenfassung

Hintergrund Es gibt kaum Publikationen über Langzeitbehandlungen von schweren rezidivierenden depressiven Episoden (MDD), die einen Zeitraum von 5 Jahren oder länger umfassen. Die meisten klinischen kontrollierten Studien dauerten nicht länger als 2 Jahre und einige neuere Studien deuteten einen Vorteil der kognitiven Verhaltenstherapie (CBT) gegenüber Antidepressiva in der Rückfallprophylaxe der MDD an.

Methode Ausschließlich ambulante „Real world“ Behandlung einer schweren Melancholie, prospektiv dokumentiert über 10 Jahre mit verschiedenen serielle Behandlungsstrategien, Absetzphänomenen und Komplikationen.

Resultate Im Vergleich zur CBT, Agomelatin, Mirtazapin, Bupropion und hoch dosiertem Milnacipran war hoch-dosiertes Venlafaxin (verlängerte Freisetzungsform, XR) wirksam, auch nachhaltig. In der Anfangszeit der Behandlung der schweren depressiven Episode wurden asymptomatische ventrikuläre Extrasystolen (englisch: premature ventricular contractions, PVC) gefunden, was zunächst zum Absetzen von hoch-dosiertem Venlafaxin (täglich 300 mg) führte. Alle oben genannten verschiedenen Behandlungsstrategien konnten die folgenden schweren Verschlechterungen der MDD (2 Rebounds, 1 Rezidiv) nicht kompensieren oder verhindern. Nur der erneute Einsatz von hoch-dosiertem Venlafaxin war erfolgreich. PVC traten nicht mehr auf und die Behandlung wurde auch über die Jahre gut toleriert, wobei der Venlafaxin-Serumspiegel zeitweise das 5-fache des empfohlenen oberen therapeutischen Referenzwertes überstieg (bekannte Bupropion-Venlafaxin-Interaktion; sonst unter hoch-dosiertem Venlafaxin etwa 2,5–3 fach erhöht). Nach Dosisreduktion oder ausschleichendem Absetzen von hoch-dosiertem Venlafaxin kam es zu eher milden Entzugssymptomen, jedoch wie oben beschrieben zu zwei Rebounds und einem Rezidiv (Recurrence).

Diskussion Diese Langzeitbeobachtung unterstützt kritische Reflexionen über den Abbruch erfolgreicher Langzeit-Behandlungen mit AD bei schwerer MDD, auch wenn diese unter „dem Schutz“ einer CBT stehen sollte. Die PVC schienen eher mit der Dauer der schweren depressiven Episode zusammenzuhängen als mit der Venlafaxin-Behandlung. Eine besondere prospektive Beobachtung dieser Längsschnitt-Fallstudie ist, dass die Rückfälle (im Sinne von Rebounds) während oder nach früheren Venlafaxin-Ausschleichmaßnahmen das spätere Rezidiv nach kompletter Genesung anzukündigen schienen. Bemerkenswerterweise konnten weder die Rückfälle noch das Rezidiv mit Hilfe der CBT verhindert werden.

Schlussfolgerung Hochdosiertes Venlafaxin hat in diesem Fall eine besondere rückfallpräventive (und „rezidivpräventive“) Wirkung bei guter Langzeit-Verträglichkeit

Keywords

melancholia - high-dosed milnacipran - antidepressants - relapse prevention - high-dose venlafaxine - therapeutic drug monitoring

Schlüsselwörter

Melancholie - hochdosiertes Milnacipran - hochdosiertes Venlafaxin - Antidepressiva - Rezidivprophylaxe - Therapeutisches Drug Monitoring

Publikationsverlauf

Eingereicht: 19. Juni 2022

Angenommen nach Revision: 16. Mai 2024

Artikel online veröffentlicht:
20. Juni 2024

• References

• 1 Leichsenring F, Steinert C, Rabung S, Ioannidis JPA. The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta-analytic evaluation of recent meta-analyses. World Psychiatry 2022; 21: 133-145
• 2 Huhn M, Tardy M, Spineli LM, Kissling W, Förstl H, Pitschel-Walz G, Leucht C, Samara M, Dold M, Davis JM, Leucht S. Efficacy of pharmacotherapy and psychotherapy for adult psychiatric disorders: a systematic overview of meta-analyses. JAMA Psychiatry 2014; 71: 706-715
• 3 Cuijpers P, Stringaris A, Wolpert M. Treatment outcomes for depression: challenges and opportunities. Lancet Psychiatry 2020; 7: 925-927
• 4 Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003; 361: 653-661
• 5 Kishi T, Ikuta T, Sakuma K, Okuya M, Hatano M, Matsuda Y, Iwata N. Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis. Mol Psychiatry 2023; 28: 402-409
• 6 Kato M, Hori H, Inoue T. et al. Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry 2021; 26: 118-133
• 7 Dobson KS, Hollon SD, Dimidjian S. et al. 2008; Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression. J Consult Clin Psychol 76: 468-477
• 8 Fournier JC, Forand NR, Wang Z. et al. Initial Severity and Depressive Relapse in Cognitive Behavioral Therapy and Antidepressant Medications: An Individual Patient Data Meta-analysis. Cognitive Therapy and Research 2022; 46: 517-531
• 9 Saunders R, Cohen ZD, Ambler G. et al. A Patient Stratification Approach to Identifying the Likelihood of Continued Chronic Depression and Relapse Following Treatment for Depression. J Pers Med 2021; 11: 1295
• 10 Claus BB, Scherbaum N, Bonnet U. Effectiveness of an Adjunctive Psychotherapeutic Intervention Developed for Enhancing the Placebo Effect of Antidepressants Used within an Inpatient-Treatment Program of Major Depression: A Pragmatic Parallel-Group, Randomized Controlled Trial. Psychotherapy and Psychosomatics 2020; 89: 258-260
• 11 Evers AWM, Colloca L, Blease C. et al. Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus. Psychother Psychosom 2018; 87: 204-210
• 12 Almohammed OA, Alsalem AA, Almangour AA, Alotaibi LH, Al Yami MS, Lai L. Antidepressants and health-related quality of life (HRQoL) for patients with depression: Analysis of the medical expenditure panel survey from the United States. PLoS One 2022; 17: e0265928
• 13 Möller HJ, Broich K. Methodik klinischer klinisscher psychopharmakologischer Therapieforschung. In: Laux G, Müller W (Editors). Psychopharmakologie und Psychopharmakotherapie kompakt. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2021. p 9-32
• 14 Laux G. Antidepressiva-Therapie in der „real world“. Erfahrungen aus der Praxis. Psychopharmakotherpie 2023; 30: 120-124
• 15 Richter LE, Machleit-Ebner A, Scherbaum N, Bonnet U. How Effective is a Web-Based Mental Health Intervention (Deprexis) in the Treatment of Moderate and Major Depressive Disorders when started during Routine Psychiatric Inpatient Treatment as an Adjunct Therapy? A Pragmatic Parallel-Group Randomized Controlled Trial. Fortschr Neurol Psychiatr 2023; 91: 297-310
• 16 Weimer K, Colloca L, Enck P. Placebo effects in psychiatry: Mediators and moderators. Lancet Psychiatry 2015; 2: 246-257
• 17 Eichler M, Pokora R, Schwenter L, Blettner M. Evidenzbasierte Medizin. Möglichkeiten und Grenzen. Dtsch Arztebl 2015; 112 A 2190-2192
• 18 Zimmerman M, Martinez JH, Young D, Chelminski I, Dalrymple K. Severity classification on the Hamilton Depression Rating Scale. Journal of Affective Disorders 2013; 150: 384-388
• 19 Bauer M, Tharmanathan P, Volz HP. et al. The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis. Eur Arch Psychiatry Clin Neurosci 2009; 259: 172-185
• 20 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 2018; 51: e1
• 21 Harrison CL, Ferrier N, Young AH. Tolerability of high-dose venlafaxine in depressed patients. J Psychopharmacol 2004; 18: 200-204
• 22 Hefner G, Hahn M, Hohner M. et al. QTc Time Correlates with Amitriptyline and Venlafaxine Serum Levels in Elderly Psychiatric Inpatients. Pharmacopsychiatry 2019; 52: 38-43
• 23 Unterecker S, Pfuhlmann B, Kopf J. et al. Increase of Heart Rate and QTc by Amitriptyline, But Not by Venlafaxine, Is Correlated to Serum Concentration. J Clin Psychopharmacol 2015; 35: 460-463
• 24 Cipriani A, Furukawa TA, Salanti G. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet 2018; 391: 1357-1366
• 25 Mago R, Tripathi N, Andrade C. Cardiovascular adverse effects of newer antidepressants. Expert Rev Neurother 2014; 14: 539-551
• 26 Montgomery SA, Prost JF, Solles A. et al. Efficacy and tolerability of milnacipran: an overview. Int Clin Psychopharmacol 1996; 11: 47-51
• 27 Periclou A, Palmer RH, Zheng H. et al. Effects of milnacipran on cardiac repolarization in healthy participants. J Clin Pharmacol 2010; 50: 422-433
• 28 Hayashi M, Mimura M, Otsubo T. et al. Effect of high-dose milnacipran in patients with depression. Neuropsychiatr Dis Treat 2007; 3: 699-702
• 29 DeRubeis RJ, Zajecka J, Shelton RC. et al. Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: A Phase 2 Randomized Clinical Trial. JAMA Psychiatry 2020; 77: 237-245
• 30 Hoffelt C, Gross T. A review of significant pharmacokinetic drug interactions with antidepressants and their management. Ment Health Clin 2016; 6: 35-41
• 31 WHO 2023 https://news.un.org/en/story/2023/05/1136367 accessed at 08/08/2023.
• 32 Pringsheim T, Kelly M, Barbui C. Stopping antidepressants following depression. BMJ. 2016; 352: i220
• 33 Lewis G, Marston L, Duffy L. et al. Maintenance or Discontinuation of Antidepressants in Primary Care. N Engl J Med 2021; 385: 1257-1267
• 34 Parker G, Paterson A. Melancholia: definition and management. Curr Opin Psychiatry 2014; 227: 1-6
• 35 Maslej MM, Furukawa TA, Cipriani A, Andrews PW, Sanches M, Tomlinson A, Volkmann C, McCutcheon RA, Howes O, Guo X, Mulsant BH. Individual Differences in Response to Antidepressants: A Meta-analysis of Placebo-Controlled Randomized Clinical Trials. JAMA Psychiatry 2021; 78: 490-497
• 36 Rotman B. Ventrikuläre Extrasystolie bei Patienten ohne strukturelle Herzerkrankung. Journal für Kardiologie – Austrian. Journal of Cardiology 2015; 22: 70-75
• 37 Dean J, Keshavan M. The neurobiology of depression: An integrated view. Asian J Psychiatr. 2017; Jun;27 101-111 Epub 2017 Jan 29. PMID: 28558878.
• 38 Henssler J, Heinz A, Brandt L, Bschor T. Antidepressant Withdrawal and Rebound Phenomena. Dtsch Arztebl Int 2019; 116: 355-361
• 39 Bschor T, Bonnet U, Pitzer M, Baethge C, Lieb K, Gertz HJ, Müller-Oerlinghausen B. Absetzen von Antidepressiva – Absetzsymptome und Rebound-Effekte: Übersicht und praktische Empfehlungen [Stopping antidepressants: withdrawal symptoms and rebound effects: Review and practical recommendations]. Nervenarzt. 2022; 93: 93-101
• 40 Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ, Weissman MM. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991; 48: 851-855
• 41 Lerner A, Klein M. Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development. Brain Commun 2019; 1: fcz025
• 42 Post RM. Heading off depressive illness evolution and progression to treatment resistance. Dialogues Clin Neurosci 2015; 17: 105-109
• 43 van Dijk DA, Meijer RM, van den Boogaard TM. et al. Worse off by waiting for treatment? The impact of waiting time on clinical course and treatment outcome for depression in routine care. J Affect Disord 2023; 322: 205-211
• 44 Berwian IM, Wenzel JG, Kuehn L. et al. The relationship between resting-state functional connectivity, antidepressant discontinuation and depression relapse. Sci Rep 2020; 10: 22346
• 45 Erdmann T, Berwian IM, Stephan KE. et al. Amygdala reactivity, antidepressant discontinuation and relapse: a longitudinal, observational study with a randomized component. PsyArXiv 2024;
• 46 Bschor T, Bauer M, Adli M. Chronic and treatment resistant depression: diagnosis and stepwise therapy. Dtsch Arztebl Int 2014; 111: 766-775
• 47 NVL Guideline Group. Härter M, Prien P. The Diagnosis and Treatment of Unipolar Depression. Dtsch Arztebl Int 2023; 120: 355-361
• 48 NVL Depression (Nationale VersorgungsLeitlinie Unipolare Depression. 2022 https://www.leitlinien.de/themen/depression/algorithmen/algorithmen-depression/nichtansprechen-therapieresistenz accessed at 08/12/2023
• 49 Qaseem A, Owens DK, Etxeandia-Ikobaltzeta I, Tufte J, Cross JT, Wilt TJ. Clinical Guidelines Committee of the American College of Physicians; Crandall CJ, Balk E, Cooney TG, Fitterman N, Hicks LA, Lin JS, Maroto M, Obley AJ, Tice JA, Yost J. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med 2023; 176: 239-252
• 50 Beck AT, Rush AJ, Shaw BF. et al. Cognitive Therapy of Depression. Guilford Press; 1979. NY. USA: