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| A) | A 50% or greater reduction in symptoms | ||
| B) | A 25% to 50% reduction in symptoms | ||
| C) | The absence of depressive symptoms or minimal symptoms | ||
| D) | The absence of meaningful response |
Treatment-resistant depression is a problem increasingly encountered by primary care and mental health providers. Most definitions of treatment response compare changes in depression rating scale scores between pre-treatment and follow-up. Standardized rating scales such as the MADRS and HAM-D are widely used to quantify treatment response [1]. The definition of antidepressant response falls into four categories [2,3]:
Remission: The absence of depressive symptoms or minimal symptoms (HAM-D score ≤7)
Response: A 50% or greater reduction in symptoms
Partial response: A 25% to 50% reduction in symptoms
Nonresponse: The absence of meaningful response (symptom reduction ≤25%)
| A) | Electroconvulsive therapy (ECT) | ||
| B) | Bright-light therapy | ||
| C) | Vagus nerve stimulation | ||
| D) | Transcranial magnetic stimulation |
Use of bright-light therapy for treatment of major depression with a seasonal specifier (seasonal affective disorder) is well established [10,11]. There is also evidence supporting its use for additional types of depressive symptom patterns, including non-seasonal depression, milder variations of seasonal depressive patterns, and depression in pregnant and postpartum women [12,13,14]. Bright-light therapy may quicken and enhance the effects of antidepressants [15]. The interaction between light intensity and duration of exposure requires two hours daily with 2,500 lux, one hour with 5,000 lux, and 30 minutes daily with 10,000 lux for efficacy [16]. Light therapy must also use equipment that eliminates ultraviolet frequencies.
| A) | Hippocampus | ||
| B) | Amygdala | ||
| C) | Dorsolateral prefrontal cortex | ||
| D) | Thalamus |
The dorsolateral prefrontal cortex is a common brain stimulation target in patients with MDD. Its normal regulatory function of control over stress and emotion reactivity is thought to be hypoactive in MDD. The dorsolateral prefrontal cortex and rostral anterior cingulate cortex areas are closely inter-connected; decreased activity in these frontal areas accounts for apathy, psychomotor slowness, and impaired executive functioning common in patients with MDD [17,18,19].
| A) | It is non-invasive. | ||
| B) | It has no side effects. | ||
| C) | It is a potent and rapidly acting treatment. | ||
| D) | It requires only one session. |
ECT remains established as a potent and rapidly acting treatment for severe or refractory MDD and is considered unrivaled among standard options for rapidly inducing antidepressant effects. ECT is effective as acute treatment, but multiple treatments are required and many who respond experience symptoms again within six months [20]. ECT generates electrical stimuli for seizure induction through electrodes applied to the scalp, with the patient under general anesthesia and pre-medicated with a muscle relaxant. Clinical outcomes are highly influenced by electrode placements, electrical intensity, and pulse width [21]. Seizure-induced changes in neurotransmitter activity, neuroplasticity, and functional connectivity account for its effects. ECT also increases brain-derived neurotrophic factor, which may promote neuroplasticity and contribute to the antidepressant effect [21,22].
| A) | Electroconvulsive therapy (ECT) | ||
| B) | Vagus nerve stimulation | ||
| C) | Deep brain stimulation | ||
| D) | Transcranial magnetic stimulation |
Vagus nerve stimulation uses an implantable device to provide intermittent stimulation to the left vagus nerve (80% afferent to the central nervous system) [2]. It received FDA approval for treatment-resistant depression in 2005 due to the lack of approved drug treatments and concerns over the long-term efficacy and safety of ECT [31].
| A) | Vagus nerve stimulation | ||
| B) | Deep brain stimulation | ||
| C) | Transcranial magnetic stimulation | ||
| D) | Magnetic seizure therapy |
With deep brain stimulation, an electrode is surgically implanted to stimulate the subgenual cingulate gyrus with high-frequency impulses to reduce depressive symptoms [2]. Deep brain stimulation is invasive and carries the risk of infection, hemorrhage, and other surgical complications. Stimulation-induced adverse effects such as facial contractions, facial paresthesias, olfactory phenomena, anxiety, and mood fluctuations have been reported, particularly at higher levels of stimulation [36].
| A) | Headache | ||
| B) | Scalp pain | ||
| C) | Seizures | ||
| D) | Cognitive impairment |
The most frequent side effects are transient scalp pain (40%) and headache (30%). Both diminish with repeated treatment and respond to over-the-counter analgesics. The cognitive safety profile is benign. Seizures are the most serious side effect, but fewer than 25 cases have been reported worldwide [21,43]. Repetitive transcranial magnetic stimulation is contraindicated in patients with any metal or metallic hardware in the head (except the mouth), with a history of seizures, and who take medications that lower seizure threshold [21,44].
| A) | Rapastinel | ||
| B) | Buprenorphine | ||
| C) | Ketamine | ||
| D) | Celecoxib |
Ketamine is anN-methyl-D-aspartate receptor (NMDA-R) antagonist that was approved for use as an anesthetic in 1970. Demonstration that a single IV dose in patients with treatment-resistant depression reliably produced rapid, robust antidepressant effects for one week was a breakthrough discovery for research and a turning point for patients for whom all other treatment approaches had failed [51]. The short-term efficacy of ketamine treatment of refractory MDD and bipolar depression is now established; over a dozen placebo-controlled trials have shown that patients with refractory MDD or bipolar depression have significantly greater response, remission, and depressive symptom reduction to single-dose IV ketamine than placebo from 40 minutes through days 10 to 12 post-treatment [52,53]. The approach has become standardized, using a sub-anesthetic dose: 0.5 mg/kg IV over a 40-minute infusion. In a 2015 analysis, ketamine was designated as one of two psychiatric treatments that had the highest potential impact on patient outcomes. This designation was based on the serious unmet need for fast-acting, well-tolerated antidepressants with efficacy in refractory MDD and bipolar depression [54].
| A) | It has psychotomimetic effects. | ||
| B) | It is administered orally. | ||
| C) | It has rapid, long-lasting antidepressant effects. | ||
| D) | It requires daily dosing. |
Rapastinel is an investigational NMDA-R partial agonist with robust cognitive enhancement and rapid, long-lasting antidepressant effects. This drug comes as a pre-filled IV syringe, administered in less than one minute. After one injection, therapeutic effects appear within two hours and last up to seven days. Rapastinel is well-tolerated, and antidepressant effects last up to 10 weeks with repeat dosing. The drug has no psychotomimetic effects, may be neuroprotective, and may enhance aspects of learning and memory. The long-lasting therapeutic benefits are explained by significant effects on metaplasticity processes in the medial prefrontal cortex and hippocampus [58,59].
| A) | Psilocybin | ||
| B) | Silexan | ||
| C) | Celecoxib | ||
| D) | Statins |
Silexan is a substance derived from Lavandula angustifolia flowers that increases extracellular serotonin levels. Approved in Germany for the treatment of restlessness related to anxious mood, its antidepressant effects were tested in a randomized controlled trial of 318 patients with mixed anxiety and depressive disorder. Silexan (vs. placebo) significantly reduced MADRS and Hamilton Rating Scale for Anxiety (HAM-A) scores. Antidepressant effects were noted after 2 weeks, became statistically significant at 4 weeks, and remained significant through the 10-week trial [63,67].