Depression in adults - Emerging treatments

Gepirone

Gepirone is an oral, selective serotonin 5-HT1A receptor agonist. Its mechanism of action is not yet fully understood. It has a different mechanism of action to selective serotonin-reuptake inhibitors (SSRIs), which block the reabsorption of serotonin into cells, meaning that it is likely to have a slightly different adverse effect profile to other treatments available for depression, notably with less potential for sexual dysfunction. It is approved by the Food and Drug Administration (FDA) for the treatment of major depressive disorder in adults on the basis of two RCTs which demonstrated superior efficacy compared to placebo, with effect sizes demonstrated similar to those of other approved antidepressants.[381] Gepirone is not yet routinely used in clinical practice. It is currently unclear whether there is a subgroup of patients who may be more likely to respond to gepirone; evidence from a follow-up analysis of clinical trial data suggests that adults with depression with prominent anxiety symptoms (anxious depression) had a greater response than those without prominent anxiety symptoms.[382] Gepirone is not approved in Europe as yet.

New and novel antidepressants

After nearly half a century in which the only standard pharmacologic treatments for depression were based on serotonin and norepinephrine neurotransmission, there has been an explosion of promising new methods emerging in the past decade.[383] A variety of new and older reformulated agents are under development; unlike traditional antidepressants, they do not all have a primary mechanism of action involving monoaminergic neurotransmission. Dextromethorphan/bupropion has been approved by the US Food and Drug Association (FDA). Dextromethorphan is the first oral N-methyl D-aspartate (NMDA) receptor antagonist (and sigma-1 receptor agonist) to be approved for the treatment of major depressive disorder. It is rapid acting, but the exact mechanism of action in the treatment of depression is unclear. Bupropion is coformulated with dextromethorphan to increase and prolong plasma levels of dextromethorphan via competitive inhibition of cytochrome P450 2D6. Approval followed two positive trial results; the first in which it demonstrated superiority to placebo, and the second in which it demonstrated superiority to bupropion alone. Of note, efficacy of dextromethorphan/bupropion was observed early in the course of treatment (at 1-2 weeks) and sustained following this.[384][385] Psilocybin, a psychedelic drug, has received breakthrough therapy designation from the FDA for treatment-resistant depression.[386] In one phase 2 trial comparing treatment with psilocybin to treatment with escitalopram, there were similar degrees of improvement in both treatment groups.[387] There is evidence that beneficial effects of psilocybin on depressive symptoms may last at least up to 12 months post-intervention in some patients.[388] A single dose psilocybin regimen has shown evidence of efficacy, according to two RCTs.[389][390] It has been suggested that the positive benefits are mediated more directly through psychologic therapy administered with psilocybin as opposed to a direct pharmacologic effect.[391] Nitrous oxide has yielded some preliminary positive results in an open trial.[392] Agomelatine, a melatonin receptor agonist and serotonin 5-HT2c receptor antagonist, has been found to be effective and is available in Europe.[393] [ ] The antibiotic minocycline has generated some positive preliminary results when used as an adjunctive treatment with antidepressants, although results are mixed.[394][395][396] Targeting minocycline toward people with depression evidence of low-grade systemic inflammation (raised CRP) is an emerging area of research.[397]

Intravenous ketamine

Intravenous ketamine, an NMDA receptor antagonist, along with its inhaled isomer esketamine (see below) have continued to perform better than placebo in alleviating depressive symptoms but are not yet used in standard clinical practice.[398][399][400][401] In case reports, case series, and select trials ketamine has been shown to have a rapid effect in the reduction of scores on several depression scales.[402][403][404] There is some evidence of a sustained antidepressant effect for up to 6 weeks.[405] Intravenous ketamine appears to be more efficacious than intranasal esketamine.[406] However, its safety and efficacy for long-term use remain unknown.[407][408] Acute side effects are common and are more likely to occur in patients given intravenous ketamine. The majority of side effects resolve shortly after drug administration. They include psychiatric (most commonly anxiety), psychotomimetic, cardiovascular, and neurologic effects. The most common somatic effects were headache, dizziness, dissociation, elevated blood pressure, and blurred vision.[409] Repeated use of ketamine in other patient groups has been linked to urological and liver toxicity, cognitive deficits, and dependency.[409]

Transcranial magnetic stimulation (TMS)

Since its introduction in 2008, TMS - the application of a magnetic field across the skull into the brain to induce electrical activity, in daily sessions over the course of 1 to 2 months - has become widely available in some clinical settings. Data support an antidepressant effect of high-frequency repetitive TMS administered to the left prefrontal cortex, and guidelines for best practice have been developed.[410][411][412] Although consensus has emerged about some aspects of the indications and application of the treatment, it remains an emerging treatment because there are many key questions about when, how, and in whom to use it. Compared with antidepressants, TMS entails a high cost in terms of both time and money. For now, it is generally reserved for patients who have not responded to antidepressants. The absence of psychosis and younger age may predict success.[410] Review of literature has found inconsistent evidence of a benefit in depression, and some evidence of a synergistic effect with concurrent antidepressant treatment.[413][414][415][416][417][418] In a durability study, TMS therapy has been shown to have durable effects and may be successfully used as an intermittent rescue strategy to prevent impending relapse.[419] Another study suggests that maintenance treatment may enhance the durability of the antidepressant effects of TMS.[420] Based on a small sample size, it appears to be safe and effective in pregnancy, although data are limited and further controlled studies are warranted.[421] Work is ongoing to establish whether variation in treatment parameters might affect outcomes.[422] Other evidence suggests that TMS is no different from sham TMS treatment in patients with depression.[423] Large-scale studies are needed.[424]

Stanford neuromodulation therapy (SNT)

SNT is a rapidly acting noninvasive brain stimulation technique, utilizing functional MRI-guided targeting, that is given over a 5-day period. It is a variant of a type of TMS utilizing intermittent theta-burst stimulation. It is approved by the FDA for adults with treatment resistant major depression, following RCT data demonstrating non-inferiority to the standard, longer TMS protocol, as well as data from an RCT of 29 adults with treatment-resistant depression who experienced an average 62% reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores following 5 days of treatment, compared to an average 14% drop in MADRS scores in the sham stimulation group.[425][426]

Vagus nerve stimulation (VNS)

VNS entails stimulation of the left cervical vagus nerve, using a commercial device.[427] The generator is programmed to deliver mild electric pulses in continuous cycles, typically with 30 seconds of stimulation followed by 5 minutes off.[428] VNS has been approved in the US for the adjunctive long-term treatment of chronic depression for patients aged ≥18 years, who are experiencing a major depressive episode and have not had an adequate response to ≥4 adequate antidepressant treatments.[429] Evidence on the efficacy of VNS is mixed.[430][431] In one long-term follow-up study, however, the benefits of VNS over treatment as usual could still be seen over 5 years.[432]

Deep brain stimulation (DBS)

A neurosurgical intervention, DBS of structures in the forebrain has had promising effects against treatment-resistant depression in a small group of individuals, but it is far from routine or low risk.[433][434] Results are limited by small sample size and insufficient randomized control data.[435][436][437]

Transcranial direct current stimulation (tDCS)

A weak electrical current is applied to the scalp, often via a cap. Similar to TMS in the localization of treatment and tolerability but uses current rather than magnetic field. While the effect size was similar to that of TMS in some studies, results from other trials have been mixed.[438][439] tDCS appears to perform better for acute depression than for treatment-resistant depression and seems to be a relatively safe option, with only minor adverse effects noted to-date.[440]

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Two systematic reviews and meta-analyses of the efficacy of NSAIDs in depression suggest they may be effective (particularly celecoxib) and safe for this indication, although results are mixed, and further work is needed to determine in which patients NSAIDs might be most effective.[441][442][443]

Buprenorphine

Buprenorphine, a partial opioid receptor agonist currently in widespread use in the treatment of opioid addiction, has shown short-term efficacy for treatment-resistant depression.[444] Long-term safety and efficacy data are lacking.

Nutraceuticals

Adjunctive use of pharmaceutic-grade nutrients, such as S-adenosylmethionine (SAMe), acetylcysteine, methylfolate, omega-3 fatty acids, vitamin D, probiotics and others, has been found to be effective in improving antidepressant response in some studies, and adds little if any risk to the patient.[445][446][447][448][449][450][451][452][453] St John’s Wort is a herb that may be effective for the treatment of mild to moderate depression.[454][455][Evidence C]What are the effects of St John’s Wort in adults with major depressive disorder compared with antidepressants?[455][Evidence C]What are the effects of St John’s Wort in adults with major depressive disorder compared with placebo?[455] However, numerous reports indicate the possibility of clinically significant drug-drug interactions, which must be taken into account if its use is being considered.[456][457] Folic acid has been of particular interest due to the observation that patients with depression have lower levels of serum folate than people without depression, including people with other psychiatric illnesses.[144] Supplementation with folic acid may be beneficial in depressed patients with folate deficiency. Folate supplementation may also be effective when added to standard antidepressant treatment in patients who are treatment naive or treatment resistant; however, results have been inconsistent.[144][458][459] One 2×2 factorial randomized clinical trial of multinutrients (omega-3 fatty acids, selenium, folic acid, and vitamin D3 plus calcium), therapy (group or individual), or their combination, given to overweight patients with subsyndromal depressive symptoms showed that multinutrients did not reduce episodes of major depressive disorder over the 1 year.[460]

Pharmacogenetics

The emergence of fast and affordable genetic assays has led to the increasing use of genetic testing to guide selection of antidepressants for depression.[461] The tests generally convey two kinds of information: some of the assays detect allelic variants of key enzymes that have proven associations with variations in treatment response; the majority delineate the variant hepatic drug-metabolizing enzymes in an individual.[462] This information does not reveal which medications an individual may find effective but rather, whether a person might require high doses of a medication (being a rapid metabolizer who excretes the drug before it can adequately perfuse the brain), or low doses (for a slow metabolizer who may find recommended drug doses to have intolerable side effects). These tests may improve outcome.[463][464] However, they have not proven to be cost-effective in practice. Pharmacogenomic analysis is not yet recommended for routine use.[465]