Depression Treatment Update

Educational Objectives

The goal of this program is to improve the management of depression. After hearing and assimilating this program, the clinician will be better able to:

1. Choose appropriate treatment options for patients with depression.
2. Optimize augmentation strategies for patients with a suboptimal response to primary depression therapy.
3. Integrate alternative therapies for postpartum depression and treatment-resistant depression.

Summary

Standard treatments for depression: include agents that act on serotonin and serotonin-norepinephrine, and tricyclic and tetracyclic agents; some drugs are approved by the US Food and Drug Administration (FDA) for children and teenagers with depression; others are considered off-label with varying degrees of supporting data; one agent (bupropion) acts on dopamine; monoamine oxidase inhibitors (MAOIs) are effective for depression but have poor patient compliance and carry a risk for drug-drug interactions; patients who take MAOIs have to make dietary changes and avoid central nervous system stimulants, depressants, and over-the-counter (OTC) cold medicines as they may lead to a hypertensive crisis; atypical drugs include mirtazapine, nefazodone, and trazodone; nefazodone's potential to cause spontaneous fulminant hepatic failure limits its use

Augmentation Strategy for Depression

Augmentation strategies: are used when an agent is not completely resolving symptoms of depression

Atypical antipsychotic agents: are not low-risk options; antipsychotics can cause tardive dyskinesia and metabolic issues; aripiprazole — approved by the US FDA; clozapine — can lower the risk for suicidal thoughts; not typically prescribed by family practitioners (FPs), but FPs may see patients taking it; a risk evaluation and mitigation strategies (REMS) registration is required for clozapine; causes serious adverse events (AEs), eg, myocarditis, increased risk for seizures because of its impact on the seizure threshold, and weight gain; olanzapine — an FDA-approved agent; available in combination with fluoxetine; because the combination is not typically covered by insurance, prescribe each drug individually; can be useful for patients with comorbid eating disorders because of the appetite stimulation caused by olanzapine, but people with eating disorders may discontinue because of weight gain; quetiapine — also approved by the US FDA but has metabolic AEs, weight gain, and sedation; FDA-approved atypical antipsychotics — among these, aripiprazole has the lowest risk for metabolic AEs but a slightly higher risk for abnormal movements; it works as a partial agonist and antagonist (increases and decreases dopamine); some antipsychotics are approved for bipolar depression but not specifically for monopolar depression

Mood stabilizers: low doses benefit people with irritable depression; have a slightly faster response rate and shorter time to steady state than the primary depression treatment options; lamotrigine — a good low-risk option for individuals with good compliance; gradually increase the dose from 25 to 50 mg for 2 wk each (4 wk total) to avoid rash; lithium — effectively lowers the risk for suicide but can cause kidney and thyroid damage; carbamazepine and oxcarbazepine — monitor a basal metabolic panel as they can cause hyponatremia; valproic acid — ie, divalproex sodium (Depakote), is used as primary augmentation therapy in limited populations; mostly used to treat people with, eg, intermittent explosive disorder; in pregnant women, it may cause neural tube defects in the embryo; ensure patients are using a good contraception strategy

Medications with limited evidence: buspirone (BuSpar, VanSpar) is helpful for people with anxious depression; liothyronine can be an augmentation strategy in patients with a normal thyroid profile; pramipexole and psychostimulants have some evidence, particularly in people with the fatigue subtype of depression while waiting for the primary depression treatment to become fully effective

Herbal supplements: there are many reviews assessing their efficacy; St. John’s Wort has many drug-drug interactions, but some limited data show efficacy over time; not much data support herbal supplements as primary depression treatment, especially in patients with significant impairment; however, some people rely on herbal supplements for transient depression symptoms, especially during times of acute stress; frequently, data show these supplements are not better than placebo; folate is required to produce dopamine, norepinephrine, and serotonin; MTHFR variance leading to folate deficiency can be treated with L-methylfolate; there is no good evidence to clarify the best dose (probably individualized); omega-3 fatty acids have a fair amount of evidence showing some benefit; S-adenosyl-L-methionine has some evidence but requires larger and longer studies; inositol (a glucose isomer), selenium, ginseng, Ginkgo biloba, chromium, and glutamine do not have data supporting them as stand-alone treatments

Suicidal ideation: the black box warning applies to all antidepressants for children, adolescents, and young adults; advise patients, particularly those <25 yr of age, to inform a physician about suicidal thoughts so they can create a good safety plan; when the boxed warning was introduced, many patients with depression were left untreated; drug overdose or suicide attempts — include taking OTC acetaminophen, ibuprofen, or naproxen; advise patients to remove guns from the home, at least for the short term, if there are safety concerns; if patients refuse this, recommend storing the gun and ammunition separately or locking firearms in a safe; suicide attempts may also involve hanging or asphyxiation through other methods and intentional or unintentional comorbid substance use, which can lead to increased impulsivity and abnormal behavior; some illegal substances are depressants (eg, alcohol)

Treatment-resistant depression (TRD): defined as adequate treatment (ie, medication or therapy) without anticipated symptom improvement; usually requires ≥2 medication trials for insurance authorization of TRD options (varies by insurer)

Ketamine and esketamine: are N-methyl-D-aspartate (NMDA) receptor antagonists; intravenous (IV) ketamine is not FDA approved; all IV ketamine clinics accept cash payment only, and monitoring is required; esketamine (Spravato) is a nasal spray that is approved for patients who have tried other treatments; requires REMS; both forms of ketamine cause AEs, eg, dissociations, dizziness, nausea, and sleepiness; ketamine clinics are designed to minimize the negative impact (eg, dim lighting, soothing sounds); negative disassociations may cause elevated blood pressure (one reason for the required monitoring); esketamine nasal spray requires 2 to 2.5 hr of monitoring in the clinic; both forms of ketamine (particularly IV) reduce suicidal thoughts; although ketamine has good data to support a reduction in acute suicidality, its use is limited because of the clinic space and monitoring requirements

Postpartum depression (PPD) treatment: uses γ-aminobutyric acid -A receptor-positive modulators; brexanolone — involves a 60-hr IV infusion with monitoring as it can cause sporadic loss of consciousness; although it is an effective treatment for PPD, the required clinical monitoring in a health care facility limits its use; REMS is required; additional AEs include sedation, dry mouth, and flushing; the black box warning applies; following the infusion, the patient is sent to inpatient psychiatry or discharged to outpatient (OP) care, depending on their response; zuranolone — a newly approved drug; this oral medication is prescribed at 50 mg, taken with food at bedtime for 2 wk; the major AE is sedation (assistance for infant care and driving is recommended); insurance coverage remains unknown; the advantage is home use without a requirement for REMS or clinical monitoring; both options are faster than the currently available antidepressants

Procedural interventions for TRD: transcranial magnetic stimulation (TMS) — an OP procedure that induces a stimulus at the dorsal prefrontal cortex; used in many depression pathways and improves depression symptoms faster and more reliably than medication trials and augmentations; used for patients in whom most other medications have failed; daily visits are needed for the first several weeks, followed by a taper; electroconvulsive therapy (ECT) — done under general anesthesia (GA); involves inducting a seizure that creates a catecholamine storm, which helps to reduce depressive symptoms; data show ECT is best for acute severe depressive episodes, PPD, and catatonia (some patients with TRD also respond); the more medication trials a patient has had, the less likely depression is to remit, even with ECT or TMS; however, 50% symptom reduction is still an improvement; a limited number of facilities perform ECT; deep brain stimulation (DBS) — requires brain surgery to implant electrodes in the brain (ie, neurosurgeon consultation); because trials are still ongoing, DBS is not yet a standard of practice; it is a permanent device

Evidence and practicalities: data supporting the efficacy of TMS are substantial, and some evidence also shows that it can help with refractory obsessive-compulsive disorder and substance use disorders; machines placement may be done manually (eg, Neurostar) or automated (eg, Brainsway); there is some physical discomfort involved, but the benefits outweigh this; sessions typically last ≈45 min, and patients receive individual attention from the technician; take-home magnetic stimulation devices are available online but lack the supporting data (although there may be a placebo effect); ECT machines — modern ECT machines have improved safety features to, eg, prevent impedance errors, reduce the risk for burns; they have a failsafe that stops the procedure unless all parameters are correctly set and impedance is as low as possible; a paralytic agent (usually succinylcholine) is used to prevent long-bone fractures from the seizure; ECT is the last and fastest option when other treatments fail or when the patient has severe catatonia

Upcoming treatments for depression: botulinum toxin — when injected at a specific site, this triggers the glabellar reflex, which makes the face appear happier by reducing frown lines; this decreases sadness through mirroring; a fair amount of data support its use; psychedelics — early studies and literature address this topic; they work by creating an internal experience and are particularly effective when combined with guided therapy; the purported mechanism is changing the internal monologue and cognitive outlook; Acero et al (2023) demonstrated that psychedelics affect neuroplasticity, and there is a placebo effect; they can target residual symptoms by targeting areas of the brain other treatments cannot reach (although not all patients respond positively to this targeting); although the practical aspects remain unknown, psychedelics affect histone-DNA methylation, mRNA, the adrenal system, the pituitary-hypothalamus axis, pain receptors, and the gut-brain axis; marijuana (cannabis) — relieves depression symptoms for some but worsens symptoms for others; early marijuana usage likely increases risk later in life because of the effects on neuroreceptor development and plasticity; the currently available strands of marijuana are more potent

Additional options: therapy — helpful if people can afford, access, and prioritize it; in-person therapy is the best option; if this is not an option, self-guided books written by, eg, psychologists, social workers, can be helpful; exercise — data show improvement of mild to moderate depression symptoms comparable with medication, with better sustainment; for patients who lack the energy to, eg, go to a gym, recommend starting with 15 min of walking twice weekly and building up from there; lifestyle modifications — family engagement, meditation, acupuncture, yoga, and online communities or support groups all have data showing improvement in mild to moderate or residual symptoms; for some people, spiritual or religious engagement (eg, counseling with pastors or church elders) may be beneficial

Readings

Acero VP, Cribas ES, Browne KD, et al. Bedside to bench: the outlook for psychedelic research. Front Pharmacol. 2023;14:1240295. Published 2023 Oct 2. doi:10.3389/fphar.2023.1240295; Besag FMC, Vasey MJ, Sharma AN, et al. Efficacy and safety of lamotrigine in the treatment of bipolar disorder across the lifespan: a systematic review. Ther Adv Psychopharmacol. 2021;11:20451253211045870. Published 2021 Oct 8. doi:10.1177/20451253211045870; Carlini SV, Osborne LM, Deligiannidis KM. Current pharmacotherapy approaches and novel GABAergic antidepressant development in postpartum depression. Dialogues Clin Neurosci. 2023;25(1):92-100. doi:10.1080/19585969.2023.2262464; Huston-Paterson HH, Mao Y, Tseng CH, et al. Rural-Urban Disparities in the Continuum of Thyroid Cancer Care: Analysis of 92,794 Cases. Thyroid. 2024;34(5):635-645. doi:10.1089/thy.2023.0357; Jeon HJ, Ju PC, Sulaiman AH, et al. Long-term Safety and Efficacy of Esketamine Nasal Spray Plus an Oral Antidepressant in Patients with Treatment-resistant Depression- an Asian Sub-group Analysis from the SUSTAIN-2 Study. Clin Psychopharmacol Neurosci. 2022;20(1):70-86. doi:10.9758/cpn.2022.20.1.70; Kaeley N, Kabi A, Bhatia R, et al. Carbamazepine-induced hyponatremia - A wakeup call. J Family Med Prim Care. 2019;8(5):1786-1788. doi:10.4103/jfmpc.jfmpc_185_19; Mortimer KRH, Katshu MZUH, Chakrabarti L. Second-generation antipsychotics and metabolic syndrome: a role for mitochondria. Front Psychiatry. 2023;14:1257460. Published 2023 Nov 24. doi:10.3389/fpsyt.2023.1257460; Peng S, Zhou Y, Lu M, et al. Review of herbal medicines for the treatment of depression. Natural Product Communications. 2022;17(11). doi:10.1177/1934578X221139082; Sub Laban T, Saadabadi A. Monoamine oxidase inhibitors (MAOI) StatPearls Publishing. 2023 Jul 17. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539848; Trifu S, Sevcenco A, Stănescu M, et al. Efficacy of electroconvulsive therapy as a potential first-choice treatment in treatment-resistant depression (Review). Exp Ther Med. 2021;22(5):1281. doi:10.3892/etm.2021.10716.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Klass’s lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Klass was recorded at Winter Family Medicine Update, held January 18-21, 2024, in Columbia, MO, and presented by the Missouri Society of the American College of Osteopathic Family Physicians. For information about upcoming CME activities from this presenter, please visit https://www.msacofp.org/events. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.50 CE contact hours.

Lecture ID:

IM713701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.