Opportunities in Managing Treatment-Resistant Depression and Tardive Dyskinesia

Psychiatric TimesVol 38, Issue 2
Volume 02

This CME describes current strategies and recent advances in treatment.


This CME is a follow-up from the 2021 Annual Psychiatric Times® World CME ConferenceTM by PER® Physicians Education Resources, LLC.

Claim Your CME Credit at gotoper.com/go/psych2021print

Treatment-resistant depression (TRD) and tardive dyskinesia are common conditions in psychiatry that present challenges in management, and in some cases may be related. Recent US Food and Drug Administration (FDA) approvals of therapies and advances in understanding these conditions provide new opportunities for improved outcomes.

Recent Additions to Treatment-Resistant Depression Options

Up to 1 in 5 American adults are estimated to meet the criteria for major depressive disorder (MDD) during their lives, and approximately 30% of individuals with MDD are resistant to conventional therapies.1,2 Although a number of definitions have been proposed for TRD, a common description is 2 or more unsuccessful trials of antidepressant agents with appropriate dosage and duration.

Guidelines from the Canadian Network for Mood and Anxiety Treatments provide an approach to patients with TRD.3 For patients with inadequate response to a first-line antidepressant, factors that support switching to another antidepressant include poorly tolerated side effects or less than 25% improvement with the initial treatment, patient preference, and reduced urgency to achieve a response (such as less severe symptoms or functional impairment).

Considerations that support adding an adjunctive therapy include a history of 2 or more antidepressant trials, good tolerance and at least 25% improvement with the initial antidepressant, and greater urgency to achieve a response.3 The guidelines suggest considering psychotherapy and neurostimulation in patients with an inadequate antidepressant response.

Therapies that may provide additional options for patients with TRD include the following:

ESKETAMINE NASAL SPRAY. In 2019, this ketamine enantiomer became the first FDA-approved therapy for TRD that targets the glutamatergic system.4 The therapy is approved for adults taking an oral antidepressant, and each 2-spray device contains 28 mg of esketamine.5 It is only available through a Risk Evaluation and Mitigation Strategy (REMS) program and bears a black box warning for sedation, dissociation, risk of suicidal thoughts and behaviors, and potential for abuse and misuse. Patients must self-administer the treatment under the supervision of a health care provider and remain for monitoring for at least 2 hours. One adverse event that is important to identify during monitoring is increased blood pressure.4,5

INTERMITTENT THETA BURST STIMULATION (ITBS). Approved by the FDA in 2018 for treating adults with TRD, iTBS provides 600 pulses of theta burst stimulation in 3 minutes, which are intended to mimic natural theta rhythms that are associated with the improved induction of synaptic long-term potentiation.6,7 The therapy demonstrated noninferiority to repetitive transcranial magnetic stimulation, delivered in 37.5-minute sessions, in 414 adults with nonresponse to an antidepressant or inability to tolerate at least 2 trials of antidepressants. The primary outcome was reduction in Hamilton Depression Rating Scale-17 score. The most common adverse events in the iTBS group were headache, fatigue, and dizziness, with a similar number of serious adverse events in both groups.7

VMAT2 Inhibitors for Tardive Dyskinesia

Tardive dyskinesia (TD) is a concern with nearly all dopamine receptor blocking agents (DRBAs), with the possible exception of clozapine.8 Though newer antipsychotics have a lower likelihood of causing TD, they are still associated with risk. A meta-analysis of randomized controlled trials comparing antipsychotic therapies used for at least 3 months found an annualized TD incidence of 6.5% with first-generation antipsychotics versus 2.6% with second-generation agents.9 Given the growing use of these drugs, the number of individuals at risk of TD may be rising.8,10

The availability of the following vesicular monoamine transporter type 2 (VMAT2) inhibitors has provided new options for improving the quality of life in patients with TD; these work by reducing the presynaptic storage and release of dopamine, without the impact of nonselective VMAT inhibition such as the bronchospasm, nausea, and hypotension that can occur with reserpine.8,10

In 2017, the FDA approved deutetrabenazine, a longer-acting version of tetrabenazine, for the treatment of TD in adults. The approval was based on the results of phase 3 studies in which most patients continued to take antipsychotic medication.8,11 Patients showed significantly greater improvement in Abnormal Involuntary Movement Scale (AIMS) score versus placebo. The most common adverse reactions in clinical trials were nasopharyngitis and insomnia.11

The agency also granted approval to valbenazine in 2017 for treating adults with TD.8 The drug was associated with significantly improved AIMS scores compared with placebo in patients who were typically continuing to use DRBAs. It is taken as a once-daily dose, and the most common adverse reaction in clinical trials was somnolence.12

In its new practice guidelines for schizophrenia, the American Psychiatric Association recommended that patients with moderate to disabling TD associated with antipsychotic therapy receive VMAT2 inhibitor treatment, preferably deutetrabenazine or valbenazine over tetrabenazine.13


1. Ruberto VL, Jha MK, Murrough JW. Pharmacological treatments for patients with treatment-resistant depression. Pharmaceuticals (Basel). 2020;13(6):116. doi:10.3390/ph13060116

2. Voineskos D, Daskalakis ZJ, Blumberger DM. Management of treatment-resistant depression: challenges and strategies. Neuropsychiatr Dis Treat. 2020;16:221-234. doi:10.2147/NDT.S198774

3. Kennedy SH, Lam RW, McIntyre RS, et al; CANMAT Depression Work Group. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. pharmacological treatments. Can J Psychiatry. 2016;61(9):540-560. doi:10.1177/0706743716659417

4. Kasper S, Cubała WJ, Fagiolini A, Ramos-Quiroga JA, Souery D, Young AH. Practical recommendations for the management of treatment-resistant depression with esketamine nasal spray therapy: Basic science, evidence-based knowledge and expert guidance. World J Biol Psychiatry. Published online November 12, 2020. doi:10.1080/15622975.2020.1836399

5. Spravato. Prescribing information. Janssen Pharmaceutical Companies; 2020. Accessed December 9, 2020. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf

6. Mendlowitz AB, Shanbour A, Downar J, et al. Implementation of intermittent theta burst stimulation compared to conventional repetitive transcranial magnetic stimulation in patients with treatment resistant depression: a cost analysis. PLoS One. 2019;14(9):e0222546. doi:10.1371/journal.pone.0222546

7. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391(10131):1683-1692. doi:10.1016/S0140-6736(18)30295-2

8. Bashir HH, Jankovic J. Treatment of tardive dyskinesia. Neurol Clin. 2020;38(2):379-396. doi:10.1016/j.ncl.2020.01.004

9. Carbon M, Kane JM, Leucht S, Correll CU. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17(3):330-340. doi:10.1002/wps.20579

10. Caroff SN. Recent advances in the pharmacology of tardive dyskinesia. Clin Psychopharmacol Neurosci. 2020;18(4):493-506. doi:10.9758/cpn.2020.18.4.493

11. Austedo. Prescribing information. Teva Pharmaceuticals USA, Inc; 2020. Accessed December 9, 2020. https://www.austedo.com/globalassets/austedo/prescribing-information.pdf

12. Ingrezza. Prescribing information. Neurocrine Biosciences, Inc; 2020. Accessed December 8, 2020. https://www.neurocrine.com/assets/INGREZZA-full-Prescribing-Information.pdf

13. The American Psychiatric Association Practice Guideline For The Treatment of Patients With Schizophrenia. 3rd ed. American Psychiatric Association; 2021. ❒

This activity is supported by educational grants from Neurocrine Biosciences, Inc. and Supernus Pharmaceuticals.

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