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Management of major depressive disorder with psychotic features

Rachel Barr, PharmD, BCPP, Ben Miskle, PharmD, and Christopher Thomas, PharmD, BCPS, BCPP

rs. C, age 56, has a history of major Based on her presentation and response, depressive disorder (MDD). She what do the data suggest about her length M has been stable for 5 years without of treatment, and when should you consider . Six months ago, she presented tapering the medication? to you, along with her son, seeking help. She reported that she had been experienc- In DSM-5, MDD with psychotic features ing , fatigue, and was not engag- is a severe subtype of MDD that is defined Vicki L. Ellingrod, ing in hobbies. Her son told you that his as a character- PharmD, FCCP had lost weight and had been avoid- ized by and/or .1 Department Editor ing family dinners. Mrs. C reported recurrent In the general population, the lifetime thoughts of dying and heard voices vividly prevalence of this disorder varies from telling her that she was a burden and that 0.35% to 1%, and the rate is higher in older her family would be better off without her. .2 Risk factors include female However, there was no imminent danger of gender, family history, and concomitant self-harm. At that appointment, you initiated .2 , 50 mg/d titrated to 100 mg/d, and , 5 mg/d. Since that time, Mrs. C has followed up Practice Points with you monthly with good response to • In patients experiencing major depressive disorder (MDD) with psychotic features, the . Currently, she states her consider electroconvulsive therapy or is much improved, and she an in combination with denies hearing voices for approximately an antipsychotic. 5 months. • Any antipsychotic can be considered for the Dr. Barr is a Clinical Psychiatric Pharmacist, Eastern Oklahoma treatment of MDD with psychotic features VA Healthcare System, Tulsa, Oklahoma. Dr. Miskle is a Clinical because there are no head-to-head trials. Psychiatric Pharmacist, University of Iowa Hospitals and Clinics, Iowa and Clinical Assistant Professor, University of Iowa College However, because second-generation of Pharmacy, Iowa City, Iowa. Dr. Thomas is Director, PGY-1 have a lower risk of and PGY-2 Residency Programs, Clinical Pharmacy Specialist in adverse effects, they should be preferred , Chillicothe VA Medical Center, Chillicothe, Ohio, and to first-generation antipsychotics. Savvy Psychopharmacology Clinical Associate Professor of Pharmacology, Ohio University is produced in partnership College of Osteopathic Medicine, Athens, Ohio. • When prescribing combination therapy, with the College Disclosures continue treatment for at least 9 months of Psychiatric The contents of this article do not represent the views of the US to reduce the risk of relapse, and consider and Neurologic Department of Veterans Affairs or the US Government. This material Pharmacists is the result of work supported with resources and the use of facilities reducing the dose of the antipsychotic cpnp.org at the Chillicothe Veterans Affairs Medical Center in Chillicothe, Ohio. medication after 1 year of treatment. mhc.cpnp.org (journal) The case presented in this article is fictional and does not represent a specific case or person(s). • When stopping antipsychotic therapy, The authors report no financial relationships with any companies implement a slow and gradual taper whose products are mentioned in this article, or with manufacturers to allow for assessment of symptom of competing products. Current Psychiatry recurrence. 30 February 2021 doi: 10.12788/cp.0092 Savvy Psychopharmacology

Epidemiologic studies have shown that setting.6 In another study, the combination psychotic features can occur in 15% to of olanzapine and was also found 20% of patients with MDD. The psychotic to be superior to olanzapine monotherapy features that occur during these episodes in reducing Hamilton Depression Rating are delusions and hallucinations.1 These Scale (HAM-D) scores.7 , when features can be either mood-congruent used in combination with , was (related to the depressive themes of worth- found to be superior to venlafaxine mono- lessness or guilt) or mood-incongruent (ie, therapy in response.8 Lastly, in unrelated to depressive themes).1 combination with either or per- phenazine has been shown to be superior to Treatment options: monotherapy.9,10 However, no medications ECT or pharmacotherapy are specifically FDA-approved for the indi- Guidelines from the American Psychiatric cation of depression with psychotic features. Clinical Point 3 Association and the National Institute for Because none of these agents have been ECT can provide Clinical Excellence4 recommend treating compared in head-to-head trials, any com- depression with with electro- bination of antidepressant and antipsychotic rapid and significant convulsive therapy (ECT) or with com- medication can be used. Due to the greater improvement in bined antidepressant and antipsychotic risk of adverse effects with first-generation patients with severe medications as first-line options. The Texas antipsychotics (FGAs), such as extrapyra- psychosis, suicidality, Medication Algorithm Project (TMAP) midal symptoms (EPS), second-generation or risk of imminent Algorithm for MDD,5 which closely antipsychotics (SGAs) should be trialed first. focuses on treatment of MDD with psy- harm chotic features, can be used for treatment How long should treatment last? decisions (see Related Resources, page 32). The optimal timeline for treating patients Electroconvulsive therapy is known to be with MDD with psychotic features is efficacious in treating patients with MDD unknown. According to the TMAP algo- with psychotic features and should be con- rithm and expert opinion, the continuation sidered as a treatment option. However, phase of pharmacotherapy should include medication therapy is often chosen as the treatment for at least 4 months with an anti- initial treatment due to the limitations of psychotic medication and at least 2 years to ECT, including accessibility, cost, and lifetime treatment with an antidepressant.5 preference. However, in certain cases, ECT The STOP-PD II study, which was a con- is the preferred option because it can pro- tinuation of the 12-week STOP-PD study, vide rapid and significant improvement in examined antipsychotic duration to deter- patients with severe psychosis, suicidality, mine the effects of continuing olanzapine or risk of imminent harm. once an episode of psychotic depression Pharmacotherapy for the treatment of had responded to olanzapine and sertra- MDD with psychotic features should consist line.11 Patients who had achieved remission of a combination of an antidepressant and after receiving olanzapine and sertraline antipsychotic medication. This combination were randomized to continue to receive this has been shown to be more effective than combination or to receive sertraline plus either agent alone. Some combinations have placebo for 36 weeks. The primary outcome Discuss this article at been studied specifically for MDD with psy- was relapse, which was broadly defined as www.facebook.com/ MDedgePsychiatry chosis. The Study of the Pharmacotherapy of 1 of the following11: Psychotic Depression (STOP-PD), a 12-week, • a Structured Clinical Interview for double-blind, randomized controlled trial, the DSM (SCID)-rated assessment that found that the combination of sertraline and revealed the patient had enough symp- olanzapine was efficacious and superior to toms to meet criteria for a DSM-IV major Current Psychiatry monotherapy with olanzapine in an acute depressive episode Vol. 20, No. 2 31 continued Savvy Psychopharmacology

plus antipsychotics are Related Resources often utilized as an initial treatment. • Texas Medication Algorithm Project. Algorithm for the Essentially, any antipsychotic agent can treatment of major depressive disorder with psychotic features. https://chsciowa.org/sites/chsciowa.org/files/ be prescribed in conjunction with an anti- resource/files/9_-_depression_med_algorithm_ , but due to the greater risk of supplement.pdf adverse effects associated with FGAs, • Dold M, Bartova L, Kautzky A, et al. Psychotic features in patients with major depressive disorder: a report from the SGAs should be trialed first. The results European Group for the Study of Resistant Depression. of the STOP-PD6 and STOP-PD II11 studies J Clin Psychiatry. 2019;80(1):17m12090. doi: 10.4088/ JCP.17m12090 have shown that once a patient responds • Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of to an antidepressant and antipsychotic, continuing olanzapine vs placebo on relapse among combination therapy needs to continue patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7): for at least 9 months to reduce the risk of Clinical Point 622-631. relapse. Thereafter, reducing the dose of When prescribing Brand Names the antipsychotic can be considered after 1 Amitriptyline • Elavil, Endep Quetiapine • Seroquel year of treatment; however, no data exist combination Fluoxetine • Prozac Sertraline • Zoloft about which agent and tapering schedule Haloperidol • Haldol Venlafaxine • Effexor therapy, continue Olanzapine • Zyprexa to consider. Because no optimal duration treatment for at least has been fully established, consider a slow 9 months to reduce and gradual taper when stopping antipsy- chotic therapy to allow for assessment of the risk of relapse recurring symptoms. • a 17-item HAM-D scoren of ≥18 • SCID-rated psychosis CASE CONTINUED • other significant clinical worsening, Based on the results of the STOP-PD and defined as having a plan or attempt- STOP-PD II trials, Mrs. C should be contin- ing suicide, developing SCID-rated symp- ued on sertraline plus olanzapine for at least toms of or , or being another 3 to 6 months before an olanzapine hospitalized in a psychiatric unit. taper should be considered. At that time, Compared with sertraline plus placebo, the risks and benefits of a taper vs continu- continuing sertraline plus olanzapine ing therapy should be considered. Given her history of MDD and the severity of this most reduced the risk of relapse over 36 weeks recent episode, sertraline therapy should be (hazard ratio, 0.25; 95% confidence inter- continued for at least 2 years, and possibly val, 0.13 to 0.48; P < .001).11 However, as indefinitely. expected, the incidence of adverse effects such as weight gain and parkinsonism was References higher in the olanzapine group. Therefore, 1. Diagnostic and statistical manual of mental disorders, 5th ed. it is important to consider the potential American Psychiatric Association; 2013. 2. Jääskeläinen E, Juola T, Korpela H, et al. Epidemiology of long-term adverse effects of continuing psychotic depression - systematic review and meta-analysis. antipsychotic medications. The STOP-PD Psychol Med. 2018;48(6):905-918. 3. American Psychiatric Association. Practice guideline for II trial showed benefit in continuing anti- the treatment of patients with major depressive disorder psychotic therapy over 36 weeks, but did (revision). Am J Psychiatry. 2000;157(4)(suppl):1-45. not answer the question of how long to 4. National Institute for Clinical Excellence. Depression in adults: recognition and management: clinical guideline continue antipsychotic therapy. [CG90]. National Institute for Health and Clinical Excellence. Published October 28, 2009. Accessed January 12, 2021. https://www.nice.org.uk/guidance/cg90 Weighing the evidence 5. Crimson ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Electroconvulsive therapy is considered a Consensus Conference Panel on medication treatment of first-line treatment option for MDD with major depressive disorder. J Clin Psychiatry. 1999;60(3): 142-156. psychotic features; however, because of Current Psychiatry 6. Meyers BS, Flint AJ, Rothschild AJ, et al. A double-blind 32 February 2021 limitations associated with this approach, randomized controlled trial of olanzapine plus sertraline vs Savvy Psychopharmacology

olanzapine plus placebo for psychotic depression: the study 9. Muller-Siecheneder F, Muller M, Hillert A, et al. Clinical Point of pharmacotherapy for psychotic depression -- the STOP- versus haloperidol and amitriptyline in the treatment PD study. Arch Gen Psychiatry. 2009;66(8):838-847. of patients with a combined psychotic and depressive 7. Rothschild AJ, Williamson DJ, Tohen MF, et al. A double- . J Clin Psychopharm. 1998;18(2):111-120. Consider stopping blind, randomized study of olanzapine and olanzapine/ 10. Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological fluoxetine combination for major depression with treatment of delusional depression. Am J Psychiatry. 1985; the antipsychotic psychotic features. J Clin Psychopharmacol. 2004;24(4):365-373. 142(4):430-436. after 1 year, but use 8. Wijkstra J, Burger H, van den Broek WW, et al. Treatment of 11. Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing unipolar psychotic depression: a randomized, doubleblind olanzapine vs placebo on relapse among patients with a slow and gradual study comparing , venlafaxine, and venlafaxine psychotic depression in remission: the STOP-PD II plus quetiapine. Acta Psychiatr Scand. 2010;21(3):190-200. randomized clinical trial. JAMA. 2019;322(7):622-631. taper

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