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Reviews

Novel Targets to Treat Depression

Opioid-Based Therapeutics

Browne, Caroline A. PhD; Jacobson, Moriah L. PhD; Lucki, Irwin PhD

Author Information
doi: 10.1097/HRP.0000000000000242

Abstract

Despite numerous therapeutics approved to alleviate symptoms of major depressive disorder (MDD), this debilitating illness remains one of the leading causes of disability and functional impairment worldwide.1 Antidepressant compounds, including selective reuptake inhibitors and tricyclic antidepressants, require weeks to months of daily oral dosing to produce remission of symptoms. However, 30%–40% of individuals fail to respond to their first trials.2–4 Moreover, these compounds remain ineffective in treating suicidal ideation and have only a moderate effect on cognitive impairment—two critical factors that dramatically impair quality of life and functionality in depressed individuals.5–8 MDD is a heterogeneous disorder with an unknown etiology.9 Most antidepressants that have been developed since the 1960s (tricyclics, monoamine oxidase inhibitors, and selective serotonin [SSRIs] and norepinephrine [SNRIs] reuptake inhibitors) were selected for therapeutic development based on their capacity to modulate monoamines, specifically increasing norepinephrine, dopamine (DA), and serotonin (5-HT) neurotransmission.10 Despite fewer side effects, increased compliance, and improved outcomes associated with more recently developed antidepressants, the odds ratio for a significant response over placebo remains modest.6 Treatment of MDD is further complicated by the co-occurrence of other disorders, including anxiety, posttraumatic stress disorder, substance abuse, and chronic pain.3,11–14 Thus, novel therapeutics to treat MDD are in urgent need.

Compounds derived from Papaver somniferum (opium poppy) and associated synthetics have been used to treat symptoms of depression for centuries.15 The practice fell out of favor since the introduction of monoaminergic-based compounds. The hypothesis that the endogenous opioid system could alleviate affective disorders has once again emerged as a potential therapeutic option. Significant advances in understanding endogenous opioid signaling provided a framework for considering the potential of selective opioid ligands and receptors in modulating the heterogeneous endophenotypes relevant to depression. Mounting evidence now suggests that targeting one or more of the four opioid receptor subtypes—delta (DOR), mu (MOR), kappa (KOR), and nociceptin/orphanin FQ (NOP) receptors—may yield effective therapeutics for stress-related psychiatric disorders.16,17 Furthermore, the rapidly acting effects of ketamine on depression and suicidal ideation may involve actions at opioid receptors.18

This review complements recently published articles summarizing the preclinical literature pertaining to the effects of KOR agonist and antagonists,19 as well as a highly detailed review of the signaling, neurotransmission, and development of opioid-based compounds.20 Specifically, this review will (1) highlight clinical evidence of dysregulated opioid signaling in the pathophysiology of depression, (2) evaluate the results from clinical trials with selective and mixed opioid compounds, and (3) consider whether these opioid compounds, like ketamine, meet the criteria for novel, rapid-acting therapeutics.

DYSREGULATED OPIOID NEUROTRANSMISSION IN MDD

MORs, KORs, DORs, and NOPs modulate a range of physiological processes and behaviors, including pain sensation, gastrointestinal function, immunity, reward, aversion, and mood.16 In this section, the association of dysregulated opioid neurotransmission on core symptoms of MDD, including depressed mood, social anhedonia, cognitive impairment, and suicidal ideation, is explored. A systematic review of the relevant literature was conducted by searching the Cochrane Central Register of Controlled Trials, CINAHL, Embase, MEDLINE, MEDLINE In-Process, PsycINFO, and PubMed from the date of their inception to 1 February 2019, with no language restrictions. The search terms “depression*” OR “mood disorder*” OR “affective disorder” were combined with each opioid receptor. The electronic database searches for relevant clinical studies/trials were supplemented with manual searches for published, unpublished, and ongoing trials in ClinicalTrials.gov using the search term “major depressive disorder” combined with the opioid receptor or the compound of interest (e.g., buprenorphine, naltrexone).

Depressed Mood and Negative Affect

Humans who have been administered KOR agonists exhibit adverse effects, including dysphoria, hallucinations, psychotomimetic effects, aversion, and negative mood.21–23 Evidence from postmortem studies conducted in subjects diagnosed with MDD show alterations of genes associated with KOR neurotransmission. Expression of the pro-dynorphin gene, PDYN, the precursor of the endogenous KOR ligand dynorphin, was decreased in depressed subjects in distinct regions of the periamygdaloid complex.24–27 Later, a large, candidate-gene analysis study of dorsolateral prefrontal cortex and anterior cingulate cortex (ACC) reported an increase of opioid receptor kappa 1 (OPRK1) gene expression in individuals with MDD.28 Conversely, downregulation of KORs in the anterior insular cortex (AIC) was evident in subjects with a history of child abuse.29 Dependent on early- and late-life stress exposure, divergent alterations in KOR expression and binding may be induced across brain regions. In the case of a severe early-life stressor such as child abuse, this stress can dynamically regulate KOR expression at an epigenetic level. The result may be a significant reduction of KOR expression in the aversion network, contributing to hyperexcitability of the network, which may develop, later in life, into a pathological condition.29 Also later in life, severe stressors such as trauma most likely augment dynorphin signaling at KORs, thus promoting a dysphoric state.

This negative affective state is common across many psychiatric disorders, prompting researchers to suggest that aberrant KOR signaling may serve as a transdiagnostic marker in stress-related disorders. This hypothesis of low KOR availability as a phenotypic marker of dysphoria was explored in neuroimaging studies.30 Positron emission tomography (PET) was used to identify changes in KOR binding potential (BP) in patients. Low KOR availability in the amygdala–ACC–ventral striatal circuit, as measured by low binding rates of the KOR antagonist radiotracer [11C]LY279505 to KOR agonists, was associated with “severity of loss” symptoms in patients with MDD, schizophrenia, and posttraumatic stress disorder.30 As [11C]LY279505 has a 4.7-fold greater selectivity for KOR over MOR,31 low KOR BP for [11C]LY279505 could represent (1) a downregulation of KORs in response to chronic stress activation or (2) high levels of dynorphin that actively compete with [11C]LY279505 binding at KORs. A later study utilized the highly selective KOR antagonist [11C]GR103535, which has 6x102-fold selectivity at KOR over MOR, and found no correlation of KOR BP in the amygdalae, hippocampi, raphe nuclei, and nucleus accumbens (NAc) of MDD subjects with depression severity, childhood trauma, or life stress.32 The study identified a trend, however, toward an association of increased cortisol levels and [11C]GR103535 binding in these subjects during exposure to a Trier social stress test.32 Moreover, elevated urinary cortisol detected in subjects with high “severity of loss” or dysphoric symptoms demonstrated increased stress reactivity in MDD subjects.30 Indeed, it has been demonstrated that unlike MOR and DOR agonists, KOR activation increases cortisol secretion in humans, nonhuman primates, and rodents.23,33–35 These data suggest an interactive relationship between dynorphin and the stress axis—namely, that exposure to a stressful stimulus augments dynorphin levels in brain nuclei associated with dysphoria, aversion, and low mood in MDD subjects, ultimately producing a negative affective state. Moreover, the increased secretion of dynorphin will heighten the release of stress hormones.

MOR BP has also been associated with depression severity. In female MDD patients who recounted an event that evoked sadness, MOR BP using the selective radiotracer [11C]carfentanil was decreased, compared to controls, in the AIC, anterior and posterior thalamus, ventral basal ganglia, amygdala, and periamygdalar cortex.36 Under similar conditions, the proinflammatory cytokine interleukin-18 (IL-18) was positively correlated with [11C]carfentanil BP at MORs during sadness-induced activation in the AIC, ventral basal ganglia, and amygdala, suggesting that neuroimmune function and MOR dysregulation are linked with depression severity.37 Furthermore, MOR BP in the posterior thalamus may be a potential biomarker for treatment response and depression severity. MDD severity was positively correlated with reduced MOR BP in the right posterior thalamus of MDD subjects when in a neutral emotional state.36 However, nonresponders exposed to ten weeks of fluoxetine treatment exhibited even greater reductions in MOR BP in the posterior thalamus relative to those who exhibited remission of symptoms at the end of the treatment period.36 Given that these studies were conducted in females, further studies are warranted to determine whether decreased MOR BP in MDD could be a sex-specific trait. Recent data suggest that increased MOR BP is a valid indicator of treatment response in both male and female MDD subjects. This hypothesis was highlighted in another study, a two-week blinded placebo trial in which subjects received an infusion of what was perceived as a rapid-acting antidepressant was followed by an open-label, ten-week trial with various SSRIs.38 Higher [11C]carfentanil binding in the NAc at baseline was measured in subjects with higher depression scores and antidepressant responsiveness. Interestingly, the response to placebo was associated with enhanced MOR BP in the ACC, thalamus, amygdala, and NAc.38 This increase in MOR BP in response to placebo is an interesting facet of MOR neurotransmission, suggesting the potential ability of MORs to reinforce treatment responses.

At present no clinical studies have evaluated DOR or NOP neurotransmission in MDD subjects. The data presented above suggest that modulation of KOR and MOR binding is associated with the severity of depression and treatment response.

Social Anhedonia and Withdrawal

Social-interaction deficits are common among individuals diagnosed with MDD.39 Often these patients and their families report withdrawal from loved ones.39 Moreover, high levels of poor social function are indicative of worse treatment outcomes.39 In healthy controls, administration of the MOR agonist morphine promoted attention to the face and eyes of others, an important component of normal social behavior in humans, whereas the mixed opioid antagonist naltrexone decreased attention paid to the eyes.40 Similarly, in response to the presentation of movie scenes of varying emotional content, MOR availability correlated negatively with hemodynamic responses to emotionally arousing scenes, as measured by functional magnetic resonance imaging (fMRI), in the amygdala, hippocampus, thalamus, and hypothalamus.41 Moreover, other social behaviors required for social-bond formation, including social laughter and social touch, were associated with an increase in MOR availability in the thalamus, ventral striatum, ACC, and AIC in healthy controls.42,43 These data establish that MOR activation is important in normal responding to social stimuli.

In a social acceptance/rejection task, depressed subjects, compared to healthy controls, showed exaggerated subjective well-being following acceptance and greater lowering of self-esteem after rejection.44 These pronounced changes in emotions were sustained in MDD subjects for a greater length of time than in controls.44 After each social-feedback session with PET, subjects rated how “sad,” “rejected,” “happy,” or “accepted” they felt. When subjects reported acceptance, the corresponding PET imaging revealed that MOR activation was significantly higher in the right AIC and left amygdala of healthy controls, but higher in the midline thalamus in MDD patients. Conversely, MOR deactivation was more apparent in the midline thalamus and subgenual ACC of healthy controls, but in MDD deactivation was evident in the left NAc.44 Increased resilience to rejection was pronounced in healthy controls and positively correlated with MOR activation during rejection in the amygdala, periaqueductal gray, and subgenual ACC.44 MDD subjects did not exhibit MOR activation in these regions during social rejection. Moreover, only in healthy controls were reports of rejection negatively correlated with MOR activation in the ACC and, following acceptance, reports of increased desire for social interaction positively correlated with MOR activation in the left NAc.44

In addition, avoidance of social attachment in adulthood was negatively correlated with MOR availability in the thalamus, amygdala, ACC, and AIC of healthy humans, highlighting the importance of these regions in establishing social interactions.45 These data reflect the lack of social attachment reported in G allele carriers of a highly penetrant single-nucleotide polymorphism (SNP) rs1799971, which results in substitution of A for G at position 118 of the OPRM1 gene and confers a loss of function of the receptor.46 Subjects with the G allele exhibited greater reactivity to social rejection in the dorsal ACC and AIC, as shown on fMRI, during an online ball-tossing game.47 In children, the G allele conferred increased withdrawal scores in response to angry expressions in an fMRI task, confirming the importance of functional MORs in mediating appropriate responses to social stimuli.48

Continued relief from the symptoms of MDD is associated with improved reward processing. Opioid neurotransmission heavily influences several important components of reward processing, which include (1) motivation: incentive salience (wanting) associated either with conscious responses for desired rewards or unconscious responses to cues, (2) hedonic impact: the pleasure derived from a reward (i.e., liking), which is influenced by subjective awareness and reward salience, and (3) learning: stimulus-dependent implicit and explicit associations.49 Less is known about KOR, DOR, and NOP availability in relation to social and nonsocial anhedonia. As reported in an earlier section, however, anhedonia across multiple disorders was associated with low KOR availability in the amygdala–anterior cingulate cortex–ventral striatal circuit.30 Social withdrawal in the context of KOR activation may reflect a failure to inhibit aversive thoughts and actions. Overall, the consensus is that modulation of MOR activation in the AIC, ACC, thalamus, amygdala, and NAc is central to promoting healthy social interactions.

Cognitive Impairment

Inadequate reward processing is also related to the cognitive dysfunction that is so pervasive in depressed subjects. The dysfunction may reflect increased distractibility due to negative affect or a pronounced bias for detecting negative stimuli. Cognitive deficits persist despite adequate treatment of negative affect.50,51 Cognitive deficits are most apparent on tasks involving emotion-dependent cognitive processes associated with blunted reward valuation, such as decision making, impulsivity, sustained attention, and psychomotor speed.52–56 Indeed, melancholic MDD subjects, compared to non-melancholic MDD subjects and controls, exhibited greater impairment in processing speed and set-shifting tasks (for sustained attention).57 Patients with a history of greater adversity and maltreatment in childhood also exhibited greater cognitive impairment in later life.58

Few clinical studies have addressed the involvement of opioid neurotransmission in cognitive processing, but it is clear that MOR and KOR agonists impair normal cognitive processes.59–61 The relationship between cognitive processing and physical movement, which is often affected in MDD, is frequently assayed using the parameter of psychomotor speed. This robust physical manifestation of poor cognitive function is sensitive to remediation with treatment. MDD subjects exhibit increased reaction time (psychomotor retardation), decreased accuracy, and impaired recall in tests of cognition. Administration of opioid agonists has been shown to recapitulate these cognitive deficits.62,63 Moreover, in healthy subjects, high doses of the opioid receptor antagonist naltrexone reduced cue-induced responding and impulsivity.64 Naltrexone increased the preference for high-value rewards over low-value rewards. Conversely, administration of low doses of the MOR agonist morphine enhanced responding for high-value rewards.65 These data suggest that value-based decision making is dynamically regulated by MORs. In support of this hypothesis, otherwise healthy subjects with the AG or GG genotype for the OPRM1 A118G SNP, compared to AA homozygotes, exhibited impaired reward responding on a probabilistic reward task.66 This deficit was characterized by a decline in the response for rewarded stimuli.66 Collectively, these findings confirm the ability of opioid neurotransmission to effectively alter these cognitive processes.

Improvement of cognitive function by opioid compounds in MDD patients has been demonstrated indirectly. In MDD patients who received electroconvulsive therapy (ECT), naltrexone administered prior to ECT greatly improved sustained attention.67 This finding is significant as ECT is associated with both anterograde and retrograde amnesia. Furthermore, opioid-dependent subjects treated with the MOR agonist/KOR antagonist buprenorphine, compared to those treated with the MOR agonist methadone, exhibited superior performances in n-back and spatial working-memory tasks.68–72 It has been suggested that buprenorphine’s beneficial effects in these cognitive tasks were mediated through KOR antagonism. In addition, clinical studies have indicated a role for DORs in modulating cognition, as a common OPRD1 polymorphism (rs678849) was associated with increased risk for mild cognitive impairment.73 Overall, these data indicate the potential of opioid antagonists to improve cognitive deficits in MDD.

Suicidal Ideation

Postmortem studies in suicide completers with a history of MDD revealed increased mRNA expression of PDYN in the patch compartment of the caudate but not in the putamen, NAc, or dorsolateral prefrontal or cingulate cortices.24,25 Within the periamygdaloid complex, decreased PDYN expression was evident in suicide completers and in several subgroups of MDD subjects who died of natural causes.26,27 Additionally, a history of child abuse was associated with lower OPRK1 expression in the AIC in depressed suicide completers.29 This decrease was driven by decreased DNA methylation of intron 2 of the OPRK1 splice variant 1. This downregulation of the KOR 1 variant was not specific to suicide but represented a causal relationship of maltreatment during childhood, with decreased AIC OPRK1 expression during adulthood in MDD subjects.29 Another epigenetic modification of KORs, an insertion/deletion at the KOR promoter region (indel, rs35566036), was also recently investigated in suicide completers.74 This indel was detected in depressed suicide completers at a greater rate than in controls (who died of accidental causes), but the increased presence of the indel did not confer a change in OPRK1 expression in the AIC, ACC, or mediodorsal thalamus.74 It is apparent from these few studies that the pattern of decreased OPRK1 expression within critical regions associated with social-bond formation, aversion, and introspection is associated with suicide completion.

Binding of the MOR agonist DAMGO in the ACC did not differentiate MDD subjects who died of other causes from those who committed suicide.75 By contrast, bipolar and schizophrenic suicide completers were found to have increased MOR availability compared to subjects diagnosed with those disorders who died of other causes.75 Interestingly, a recent study indicated that patients who possess one or two copies of the G allele of the loss-of-function OPRM1 A118G SNP had less treatment-emergent suicidal ideation than A allele carriers.76 Almost 78% of the 112 subjects who exhibited treatment-emergent suicidal ideation had two copies of the A allele.76 This subject population was more likely to be male, have comorbid alcohol use disorders, use benzodiazepines, and have a lifetime history of suicide attempts.76 These characteristics suggest that compounds with MOR antagonism have the potential to be effective agents for suicidal ideation, either alone or in combination with currently used therapies. Although no postmortem studies of depressed suicides have explored alterations in DOR function, a significant decrease in nociceptin/orphanin FQ mRNA was apparent in the dorsal ACC of suicides.77

Collectively, these studies support the association of aberrant KOR, NOP, and MOR neurotransmission with the pathophysiology of suicide completion. These data also provide a basis for suggesting that KOR and NOP neurotransmission should be considered as targets to treat suicidal ideation.

THERAPEUTICS TARGETING OPIOID RECEPTORS

The next section will consider the current status of opioid-based compounds that have reported positive effects in clinical studies (Table 1). Many of these studies describe rapid and sustained alleviation of severe, unremitting depression in treatment-resistant patients by opioid-based compounds. The rapid onset of clinical effects should commend opioid compounds as superior relative to other antidepressants, which require weeks to months of treatment prior to demonstrating therapeutic efficacy.

Table 1
Table 1:
Opioid-Based Compounds Reporting Positive Effects in Clinical Studies

JNJ-67953964

The aminobenzyloxyarylamide JNJ-67953964 (named recently as aticaprant, formerly LY2456302 and CERC-501) is a selective KOR antagonist originally developed by Eli Lily. It is 6.3- and 34-fold more selective for KORs than MORs and DORs, respectively.99,100 The extensive preclinical and clinical work performed to establish the selectivity of JNJ-67953964 for KORs will not be detailed here. Unlike the long-lasting KOR antagonists, JDTic and nor-binaltorphimine (nor-BNI), JNJ-67953964 was rapidly absorbed and eliminated within 48 hours of oral administration.101 These findings corresponded with PET imaging data obtained from healthy human controls demonstrating dose-dependent receptor occupancy, with 35% and 95% of receptors occupied at 0.5 mg/kg and 10 mg/kg, respectively.102 Occupation of KORs by JNJ-67953964 was 19% with 0.5 mg/kg and 72% with 10 mg/kg 24 hours post-administration. Binding was highest with the 0.5 mg/kg dose in the hippocampus. As expected, the higher dose of JNJ-67953964 (10 mg/kg) resulted in a more evenly distributed pattern of KOR occupation within the hippocampus, cingulate cortex, caudate, and amygdala.102 The increased binding in the hippocampus may reflect a greater density of KORs in the hippocampus than in other brain regions. Overall, these data demonstrate KOR binding in brain regions implicated in the pathophysiology of depression.

Preclinical studies demonstrated a comparable effect of JNJ-67953964 with the antidepressant imipramine in screening tests for antidepressant drugs in mice.99 Reduced anxiety-like behavior 24 hours after a single injection in a rodent behavioral test that requires chronic treatment with SSRIs or SNRIs to evoke a similar response was also reported.103 Moreover, low-dose JNJ-67953964 (1 and 3 mg/kg, by mouth) combined with low-dose citalopram (5 mg/kg, injection) elicited a larger anxiolytic effect in mice, compared to those treated with JNJ-67953964 or imipramine alone.99 These data collectively provide evidence supporting the clinical evaluation of JNJ-67953964 in treating depression and anxiety. Our laboratory has confirmed the effects of JNJ on screening tests for antidepressant drug effects.8 We have also found that JNJ reversed reductions of sucrose preference, anxiety, and social interaction produced by unpredictable chronic mild stress (unpublished).

As part of the National Institutes of Mental Health FAST-FAIL initiative, a phase 2a double-blind, parallel-group, placebo-controlled, proof of mechanism study (NCT02218736) evaluated the effects of eight weeks of JNJ-67953964 (10 mg) in individuals satisfying the symptoms of anhedonia under the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (Table 1).78 JNJ-67953964 demonstrated greater ventral striatal activation, measured by fMRI, during the monetary incentive delay task.78 These data confirmed the ability of JNJ-67953964 to modulate this critical hub of reward processing. A secondary measure included improved clinical anhedonia on the Snaith-Hamilton Pleasure Scale (SHAPS) following JNJ-67953964 treatment. Based on these data, the Fast-Fail Trials Program has approved the continued clinical evaluation of JNJ-67953964 for treating MDD.78

BTRX-246040

The highly selective NOP receptor antagonist BRTX-246040 (formerly LY-2940094) readily penetrates the human brain, with optimal drug levels detected in plasma between 2 to 6 hours posttreatment.79,104 Although significant species differences have been reported for N/OFQ expression, localization, and density of NOPs in rodents, primates, and humans, the pattern of receptor occupancy of BTRX-246040 is comparable between rodents and humans.105–110 In studies conducted in both human and rodent brains two hours following BRTX-246040 administration, approximately 80% of NOP receptors were occupied across the prefrontal cortex (PFC), occipital cortex, putamen, and thalamus.111 Given the preclinical evidence demonstrating robust effects of BTRX-246040 in rodent tests that predict antidepressant potential and the demonstration of anti-stress effects in rodent models of stress, a proof of concept study for BTRX-246040 in depressed human patients reported a nonsignificant reduction in Hamilton Depression Scale (HAM-D)–17 scores following eight weeks of oral treatment (Table 1).112 Although the primary endpoint (reduced HAM-D-17 scores) was not achieved in that study, patients treated with BTRX-246040, relative to those treated with placebo, did exhibit greater emotional processing of positive stimuli and large reductions in depressed mood. These data support the further investigation of BTRX-246040 to treat MDD.79 As such, several clinical trials evaluating BTRX-246040 in MDD subjects are ongoing: NCT01724112, NCT01404091, and NCT01263236.

AZD2327

Localization of DORs is conserved across species, and just like the other opioid receptors, PET ligand binding using [(11)C]methylnaltrindole has identified the highest levels of DOR binding in the amygdala, putamen, and temporal, insular, occipital, frontal, and cingulate cortices, all of which are regions associated with the development and treatment of psychiatric disorders.113–120 Efforts to develop DOR agonists for clinical use have struggled to separate the convulsant and sedating effects of these compounds from their antidepressant effects and to improve permeability across the blood-brain barrier. Clinical studies have now demonstrated the safety and efficacy of several DOR agonists. Encouraged by the successful preclinical data obtained from assays of defeat, learned helplessness, and anxiety in rodents, the highly selective DOR agonist 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327) was assessed in subjects diagnosed with anxious MDD.80 This study identified decreased vascular endothelial growth factor (VEGF) levels and elevated EEG gamma power compared to those treated with placebo.80 Although AZD2327 did not modify depression as measured by the HAM-D score, there were robust changes in Hamilton Anxiety Rating Scale scores (Table 1), suggesting that AZD2327 would be more beneficial in treating anxiety. Doses were limited in this study because of the concern for seizures. This concern could limit the clinical effects of DOR agonists unless compounds without seizure potential are tested. Still, these studies support the continued clinical evaluation of DOR ligands as therapeutics for MDD and anxiety.

Additionally, given the strong analgesic effects of DORs in preclinical studies, compounds like AZD2327 may produce the most beneficial effect in MDD patients with comorbid chronic pain. Similarly, preclinical studies consistently report dramatic reductions in anxiety-like behavior and addiction; consequently, the utility of these compounds in treating comorbid anxiety and substance use disorder may represent a significant application of DOR agonists as therapeutics for stress-related disorders.

Buprenorphine

Buprenorphine is an Food and Drug Administration (FDA)-approved treatment for opioid use disorder and chronic pain.121 Unlike methadone, buprenorphine is a partial MOR agonist, reducing the effects of other opioids on euphoria and respiratory depression.122 Individuals suffering from opioid use disorders are maintained with high doses of buprenorphine (16–32 mg/day). However, the doses used to treat MDD in opioid-naive patients are ten-fold lower (0.2–4 mg/day). In healthy human subjects administered low-dose buprenorphine, there was a bias toward greater processing of positive stimuli. This effect occurred in the absence of a subjective high, suggesting that the beneficial effects of buprenorphine are not primarily mediated by its MOR agonist activity.123,124 Indeed, buprenorphine has activity at multiple opioid receptors.121 In particular, the analgesic effects of buprenorphine are mediated not only by MOR partial agonism, but also by modulation of KORs, DORs, and NOPs. In the context of depressed mood, however, the high affinity and efficacy of buprenorphine as an antagonist of KORs has been hypothesized to underlie the beneficial effects of buprenorphine.125 This hypothesis has been tested in preclinical studies and yielded important information regarding mechanism of action on different behavioral measures. In studies conducted in rodent models of stress on endpoints used to elucidate antidepressant potential, it was confirmed that KOR antagonism underlies the ability of buprenorphine to alleviate negative affect and promote anti-stress effects.103,125–128 Critically, this study also demonstrated that expression of Oprk1 and Oprm1 in the amygdala, cortex, hippocampus, and striatum was restored to control levels in mice exposed to stress treated with buprenorphine.125 Buprenorphine exhibits a second prolonged phase of slow dissociation from the MOR receptor, resulting in a period of functional blockade of MORs.129,130 This latent MOR blockade mediates buprenorphine’s activity on tests of anxiety.127,131 Remarkably, following a single injection in rodents, low-dose buprenorphine exerts behavioral effects that are sustained at time points when desipramine and MOR agonists no longer produce alterations in behavior.126 Moreover, in tests that require chronic administration of antidepressants to produce a positive effect, the ability of buprenorphine to produce beneficial behavioral effects in rodents recapitulates buprenorphine’s clinical effects following a short period of treatment.

Clinical studies have evaluated the beneficial effects of buprenorphine on measures of depression in subjects with opioid use disorder and in opioid-naive MDD patients (Table 1). Low-dose buprenorphine (0.2 mg morning and evening, sublingual) produced significant improvements in mood of MDD subjects over the course of one week in five of ten subjects treated, suggesting that relief of symptoms may occur more rapidly than with other antidepressant medications. Following discontinuation, however, depressive symptoms did return.81 In severely ill, treatment-resistant depressed patients, HAM-D scores were reduced following just one week of treatment (0.45 mg/day to 3.6 mg/day), with four of five patients achieving remission at the end of the four- to six-week treatment period.83 Similarly, remission was achieved with one week of buprenorphine (sublingual 0.8–2.0 mg/day) treatment in a small number of severely depressed individuals. Following completion of the study, five of six patients had complete remission of symptoms.84 Collectively, these studies identified the potential of buprenorphine to rapidly treat subjects with intractable MDD without comorbid substance use disorder. In line with this hypothesis, an open-label, eight-week trial conducted in elderly, venlafaxine treatment–resistant depressed patients (Montgomery-Åsberg Depression Rating Scale (MADRS) score = 27; SD = 7.3; range, 18–42) determined that buprenorphine (mean daily dose = 0.4 mg/day; SD = 0.21; range, 0.12–0.83) dramatically reduced depressive scores to 9.5 (SD = 9.5; range, 0–33) at the end of the treatment period.87 The effects of buprenorphine were evident by the end of week 3. The robust alleviation of MADRS scores was greatly influenced by the effect of buprenorphine on ratings of sadness and pessimistic thoughts.87 Improvements in psychomotor speed, improved recall, and word discrimination were also evident when these individuals underwent cognitive evaluation posttreatment. Importantly, no withdrawal was evident in subjects throughout the four-week post-discontinuation follow-up period.87 Moreover, short-term, low-dose buprenorphine treatment has also been shown to produce significant and rapid attenuation of suicidal ideation.57,132 Overall, these data clearly demonstrate the efficacy and potential of buprenorphine to rapidly alleviate depressed mood, cognitive impairment, and suicidal ideation.

Despite the efficacy of buprenorphine in MDD subjects, valid concerns remain about the safety of buprenorphine in this vulnerable patient population.133 To minimize the abuse potential and diversion of buprenorphine, alternative routes of administration include depot injection, subcutaneous implant, or micropatch. However, the efficacy of buprenorphine for MDD via these routes has not been evaluated in clinical studies. Going forward, the risk/benefits of using buprenorphine in suicidal or treatment-resistant patients should be reassessed, as evidence continues to mount in support of buprenorphine’s efficacy in treating intractable depression and suicidal ideation.

ALKS-5461

Harnessing the beneficial antidepressant effects of buprenorphine and mitigating its abuse potential prompted the development of ALKS-5461 (Table 1), a combination of buprenorphine with the MOR antagonist samidorphan.134–136 Preclinical studies have indicated that samidorphan administered alone does not alter neurochemistry, in general, or immobility in the forced swim test.137 As such, it is postulated that the MOR antagonism produced by samidorphan does not contribute to the beneficial effects of ALKS546; instead, it acts solely to counteract the rewarding effects of buprenorphine. However, a direct comparison of buprenorphine alone versus ALKS4561 in depressed subjects has not been conducted.

Overall, the clinical studies have determined that a 1:1 buprenorphine:samidorphan ratio produced the optimal effect on endpoints for MDD remission and mitigation of MOR agonist activity. In trials conducted in opioid-experienced individuals and in those experiencing a current treatment-refractory depressive episode (Table 1),91 the 1:1 ratio combination produced no sedation and no subjective high in the individuals tested. This combination of buprenorphine/samidorphan yielded a robust reduction of ratings on HAM-D scores after one week of treatment, with no withdrawal symptoms observed following discontinuation.91

ALKS-5461 markedly improved HAM-D, MADRS, and the Clinical Global Impressions severity scale scores when administered to individuals with inadequate/partial response to SSRI or SNRI treatment.92 These robust improvements were reported after four weeks of daily treatment with buprenorphine 2 mg and samidorphan 2 mg.92 ALKS-5461 was designated as a Fast Track Designated Medicine by the FDA in October 2017, but the subsequent Focused on Results with A Rethinking of Depression (FORWARD) trials did not yield the evidence required to gain approval as a therapeutic drug for depression. FORWARD-1 and FORWARD-2 demonstrated the safety of ALKS-5461, with no overt signs of withdrawal or tolerance developing in study subjects.91–93 The FORWARD-3 study failed to meet the pre-specified primary efficacy endpoint.94 Despite positive effects reported in the FORWARD-4 and -5 trials in February 2019, the FDA ruled that additional studies are needed to confirm the usual efficacy. At present, clinical studies have been initiated to provide additional support for the drug (NCT03188185 and NCT03610048).

Despite these setbacks, the promise of yielding a novel therapy for depression derived from buprenorphine’s unique pharmacological profile in combination with a MOR antagonist should embolden the field to pursue other opioid compounds for treating MDD and other stress-related psychiatric disorders.

Naltrexone

Naltrexone, is a nonselective opioid antagonist, with a 10- to 25-fold higher affinity for MORs over KORs and DORs.138 It is an FDA-approved treatment for alcohol and opioid use disorders. Naltrexone has shown efficacy in alleviating depression when used as an adjunct therapy (Table 1). In particular, low-dose naltrexone (1 mg, twice daily for three weeks) augmented the response to the dopaminergic antidepressants aripiprazole (2.5 mg/day), bupropion (300 mg/day), and sertraline (150 mg/day).139

Reminiscent of buprenorphine’s remediation of depression in patients with comorbid opioid use disorders, most studies that reported naltrexone’s beneficial effects on depressive scores were conducted in subjects with substance use disorders.140 Across numerous studies, naltrexone consistently alleviated depression, anxiety, and insomnia in opioid-dependent individuals.90,93,97,98 In addition, naltrexone effectively decreased HAM-D scores of individuals diagnosed with comorbid bipolar disorder and alcohol use disorder.141 Clinical evaluation of the antidepressant activity of naltrexone administered to opioid-naive MDD subjects as the sole therapy has not been conducted. The previously reported findings provide a clear rationale for investigating the effects of naltrexone for treating MDD in opioid-naive, depressed patients.

Ketamine has recently been approved by the FDA as a treatment for MDD based on its properties of producing a rapid (within hours) and protracted alleviation of depressed mood and suicidal ideation.142 The exact mechanism through which ketamine exerts its antidepressant activity remains unclear, but recent evidence suggests that opioid receptors may play a role. Naltrexone (50 mg) administered to a small cohort of 12 subjects effectively blocked ketamine’s antidepressant effects.18 Dissociative symptoms associated with ketamine infusion persisted despite opioid blockade. Together, these data suggest that endogenous opioid tone is involved in remediating depressive symptoms but does not contribute to the psychomimetic effects of ketamine. Naltrexone has affinity for both MORs and KORs. However, the contribution of these receptors to the blockade of ketamine’s effects was not empirically tested.143,144 This study has evoked both controversy and excitement in the field and has helped to accelerate interest in the potential of opioid modulation in treating MDD.

RAPID-ACTING ANTIDEPRESSANTS: SHARED MECHANISMS

The long-accepted limitation that most antidepressant treatments require weeks of treatment prior to therapeutic onset has recently been challenged by the discovery that ketamine and ketamine-like compounds can alleviate depressive symptoms within hours of treatment.145 As indicated in the previous section, opioid-based compounds can dramatically reduce clinical depression scores within the first week of treatment. However, the exact mechanism through which such rapid relief from symptoms could occur is unknown. This section will highlight some of the key molecular and neurochemical changes hypothesized to underlie ketamine’s antidepressant activity. Some of these effects are also shared by opioid-based compounds and may be responsible for rapid onset of effects (see Figure 1). This evidence has been largely derived from preclinical studies that have generally recapitulated the clinical observations indicating the potential antidepressant properties of opioid receptor ligands.20,146,147

Figure 1
Figure 1:
Modulation of glutamate release in the PFC by Opioid-Based Compounds. Panel A illustrates the opioid receptors that inhibit neurotransmission in the raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area VTA. The dynamic regulation of these monoamines by opioid receptors modulates glutamatergic tone in discrete regions of the prefrontal cortex (PFC), including the anterior cingulate cortex (ACC), prelimbic cortex (PL), and infralimbic cortex (IL). Enhanced glutamatergic neurotransmission in the PFC ultimately restores stress-induced impairments in PFC regulation of subcortical regions associated with reward, cognition, and negative affect, including the hippocampus (HIPP), nucleus accumbens (NAC), and amygdala (AMY). DOR, delta opioid receptor; KOR, kappa opioid receptor; MOR, mu opioid receptor; NOP, nociceptin/orphanin FQ receptor. Panel B depicts the proposed alterations produced by KOR antagonists on 5-HT modulation of PFC glutamatergic neurotransmission. The administration of a KOR antagonist reverses stress-induced KOR inhibition of 5-HT on DRN-PFC projecting neurons and cortical GABAergic interneurons. The resultant increase in 5-HT release evokes firing of layer V glutamatergic pyramidal cells. This surge in glutamate release produces an increase in BDNF release and trafficking of AMPA receptors to the cell surface, promoting synaptogenesis. Ultimately, this process restores PFC glutamatergic regulation and favors synaptogenesis in a key brain region implicated in MDD. 5-HT, serotonin; AKT, protein kinase B; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; βArr, β arrestin; BDNF, brain-derived neurotrophic factor; Ca2+, calcium; CREB, cAMP response element−binding protein; DA, dopamine; DAG, diacylglycerol; ERK, extracellular signal–related kinase; Grb1, growth factor receptor–bound protein 1; GAB1, GRB2-associated binding protein 1; GSK3, glycogen synthase kinase 3; MEK, mitogen-activated protein kinase; NMDA, N-methyl-D-aspartate; PIP2, phosphoinositol 3 kinase, phosphatidylinositol (3,4)-bisphosphate; PKC, protein kinase; RAF, protooncogene RAF 1; Shc, transforming protein 1; SOS, Son of Sevenless; TrkB, tyrosine receptor kinase B.

Ketamine has two phases of activity. The first, which occurs immediately during infusion, is caused by robust alterations in glutamatergic neurotransmission.148,149 Specifically, ketamine targets cortical N-methyl-D-aspartate (NMDA) receptors localized on gamma-aminobutyric acid (GABA) interneurons to promote disinhibition of GABA on glutamate release.149 The elevated release of glutamate promotes a period of active protein translation, augmented synaptogenesis, and increased neuronal plasticity, including the release of molecular mediators such as brain-derived neurotropic factor (BDNF).150 It is these plastic changes and the subsequent upregulation of other glutamatergic receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and metabotropic glutamate receptors that is proposed to underlie the period of protracted and sustained behavioral effects associated with a single infusion of ketamine that lasts for days after.151 This framework provides important considerations for the investigation of opioid mechanisms in depression.

Glutamate Plasticity and Cortical Monoamine Neurotransmission

Ketamine administration suppresses GABA interneurons and promotes glutamate and amine efflux in the thalamus, cortex, and other limbic structures of importance in the onset and remediation of MDD.152–154 These hallmarks of ketamine’s antidepressant effects are also modulated by opioidergic tone.

Extracellular release of serotonin by dorsal raphe nucleus (DRN) terminals modulates cortical glutamatergic neurotransmission indirectly through GABAergic interneurons and directly at the level of DRN cell bodies.155–157 During chronic stress exposure, there is increased inhibition of 5-HT neurotransmission following activation of KORs and NOPs. Indeed, 5-HT tissue content in the cortex was reduced by N/OFQ administration under anxiogenic conditions.158 Under these same conditions, N/OFQ elevated 5-HT1A receptor density, but a decrease in affinity may have occurred to compensate for the increase in receptor number.158 KOR activation results in the inhibition of 5-HT excitability of presynaptic neurons under stress, resulting in a net decrease of 5-HT release.159 Repeated stress actually decreases the ability of KORs to activate postsynaptic G-protein-gated inwardly rectifying potassium channels (GIRKs), which is hypothesized to result from the repeated release of dynorphin during stress exposure.159 KOR activation further reduces 5-HT neurotransmission by promoting the internalization of the serotonin transporter, ultimately decreasing 5-HT stores in the presynaptic neurons.160 These changes contribute to an overall reduction in cortical 5-HT and its ability to modulate glutamatergic neurotransmission.

Figure 1B depicts the potential alterations induced by the administration of a KOR antagonist in the context of stress. Via the blockade of KOR-mediated inhibition of 5-HT from DRN-PFC projecting neurons, there is an overall increase in 5-HT release in the PFC. The most prevalent types of 5-HT receptors in the PFC are 5-HT1A, 5-HT2A, and 5-HT3. Of these receptors, 5-HT2A is represented in this schematic. Located on cortical layer V pyramidal cells, 5-HT2A receptors rapidly evoke glutamate release and gate AMPA plasticity within the PFC in rodents.161 Reductions in the number of 5-HT2A receptors is consistently associated with chronic administration of SSRIs and their behavioral effects in preclinical studies.162 However, it is the dynamic alterations in synaptogenesis promoted by 5-HT2A receptor activation by hallucinogenic compounds, including ketamine, that may be key to evoking a rapid-acting antidepressant response. The low-level activation of 5-HT2A can stimulate a surge in glutamate, producing an increase in BDNF release, trafficking of AMPA receptors to the cell surface, and promoting synaptogenesis. Ultimately, this process restores normal PFC glutamatergic function associated with lessening the disabling symptoms of MDD.

Another critical neurotransmitter in the treatment of MDD is dopamine. A substantial literature in the field of substance use disorders pertains to DA neurotransmission by MORs, DORs, and KORs.17,163–166 In relation to the emergence of negative affect following stress exposure, the modulation of MORs, activation of DORs, and blockade of KORs may normalize DA release from ventral tegmental area (VTA)–PFC projecting neurons. Acute stress evokes an increase in DA efflux within the medial PFC (mPFC). Simultaneously, the activation of glucocorticoid receptors within the mPFC following acute stress has been demonstrated to reduce activity of glutamatergic VTA projecting neurons, decreasing the stress-evoked DA efflux in the mPFC.167 Control of stress-evoked DA in the mPFC is attributed to a selective number of KOR immunoreactive DA neurons that project from the VTA to the mPFC.168 Activation of these KOR positive, VTA–PFC projecting DA neurons decreases DA release. Furthermore, VTA D2 receptor function is diminished by KOR activation, contributing to a further reduction of DA release within the mPFC during stress.168 Chronic stress increases the expression of both DA D1 and D2 receptors in the mPFC.169,170 These alterations in pyramidal DA D1 receptors resulted in elevated frequency of miniature excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs).169 DA D2 receptor-containing neurons, however, exhibited a significant reduction in their EPSCs.169 Ultimately, these alterations continue to suppress the firing of glutamatergic pyramidal neurons within the PFC.171 The strength of DA D1-mediated long-term potentiation, as well as DA D2-evoked long-term depression, is known to be modulated by KORs.172 VTA GABAA-evoked IPSCs are consistently reported following stress; they are sensitive to inhibition by the activation of DORs.173 Curiously, this effect is further modulated by glucocorticoid receptors. Animals with high levels of corticosterone exposed to foot shock did not exhibit DOR agonist [D-Pen]-enkephalin (DPDPE)–induced reductions in GABAA-evoked IPSCs within the VTA; in this case the number of IPSCs increased.173 Conversely, DPDPE administration in stressed rats with lower corticosterone levels inhibited VTA GABAA IPSCs.173 These data highlight the importance of considering the individual stress response of subjects when exploring the effects of opioid ligands. Given the importance of these DA glutamatergic interactions within the PFC, experiments that explore the role of DORs and KORs on these interactions under stress conditions are clearly warranted.

Activation of MORs has been consistently demonstrated to elevate glutamate within the mesolimbic DA circuit174 and to attenuate DA efflux in cortical terminals.164 Indeed, ketamine has agonist activity at MORs, which is important in producing the analgesic action of ketamine.143 Moreover, the partial MOR agonist buprenorphine produces marked reductions on intractable depression (see previous section), although the beneficial effects of buprenorphine at MOR are most likely due to its latent MOR antagonist effects. Similarly, the MOR antagonist naltrexone produces beneficial behavioral effects on the depression of opioid-experienced subjects. More extensive preclinical evaluation of MOR antagonists on outcomes relevant to depression and anxiety are warranted.

It will be extremely difficult to rationalize the use of MOR activators for medical purposes without a significant risk-benefit assessment. Of note, however, is the role of MORs in producing tianeptine’s effects on glutamate neurotransmission. Tianeptine is an atypical antidepressant with full agonist activity at the MOR.175 Like ketamine, tianeptine increased p-SER845 GluA1–containing AMPA receptors in the CA3 region of the hippocampus and frontal cortex following chronic administration in stress-naive animals.176 Moreover, tianeptine normalized stress-induced elevations in extracellular glutamate release within the basolateral amygdala following acute-restraint stress and chronic stress exposure.176 Within the central nucleus of the amygdala, repeated stress produced a dramatic reduction in vGLUT2 expression, which was restored following tianeptine administration.177 Tianeptine also reversed chronic restraint stress-induced increases in the NMDA:AMPA/kainate ratio and hyperexcitability in the CA3.178

Many of the opioid-related compounds under clinical investigation for the treatment of MDD have been shown to produce neurochemical effects that are similar to those of ketamine. It has been shown that buprenorphine (3 mg/kg) can elevate glutamate levels in the NAc of rats.179 Moreover, naltrexone increased GluA1-S845 phosphorylation–dependent AMPA trafficking.180 In addition, DOR activation has been shown to increase mRNA and protein expression of astrocytic excitatory amino acid transporters (EAATs) 1 and 3, enhancing the uptake of extracellular glutamate.181 Collectively, these findings demonstrate that MOR, DOR, and KOR engagement in the context of stress can recapitulate ketamine-mediated alterations in molecular correlates of antidepressant activity.

Opioids modulate glutamatergic neurotransmission across multiple brain regions that affect cortical efflux of amines. Substantial research efforts are currently under way to establish the effects of the opioid compounds reviewed herein on the specific hallmarks of glutamatergic signaling that are associated with ketamine’s antidepressant activity.

Mitogen-Activated Protein Kinases

Opioid receptors belong to the superfamily of 7-transmembrane-spanning G-protein-coupled receptors (GPCRs), coupled to inhibitory heterotrimeric Gαi/o proteins.182 Following opioid receptor activation, Gβγ dissociation upregulates K+ conductance through the inwardly rectifying K+ channel Kir3, while downregulating voltage-dependent Ca2+ channel activity.183–188 Gβγ also induces arrestin-dependent upregulation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38.189 These kinases are necessary for the transfer of signals from receptors at the cell surface to the transcriptional machinery in the nucleus—as required to modulate neuronal survival and synaptogenesis.

Aberrant neuronal firing and synaptic plasticity deficits are characteristic features of rodent models of stress and depression.7,16,190,191 A growing number of animal studies have highlighted the importance of these signaling pathways in alleviating depression.192 Specifically, activation of ERK signaling is observed following chronic administration of antidepressants and is critical for the effective reversal of stress-induced behavioral deficits.192–197 More rapid-acting therapeutics such as electroconvulsive shock and ketamine have also been shown to activate ERK signaling.198–201

Cell type–specific regulation of opioid-mediated ERK signaling has been reported. In astrocytes, the Gβγ dissociation following KOR activation induces calcium-dependent pyruvate dehydrogenase kinase 1 (PDK-1) phosphorylation of phosphoinositide-3-kinase (PI3K), which in turn activates protein kinase C zeta (PKCζ)–dependent phosphorylation of ERK1/2.202–204 Conversely, MOR activation upregulates ERK1/2 phosphorylation via PKCε in a Ca2+-independent manner through phospholipase C (PLC)–mediated upregulation of diacylglycerol (DAG).203 Sustained MOR and KOR activation have divergent effects on ERK within astrocytes. Acute activation by the MOR agonist DAMGO produced transient pERK1/2 upregulation lasting less than 30 minutes. By contrast, chronic MOR activation produced a 30%–40% decrease in pERK1/2, but chronic KOR activation by the agonist U69,593 maintained ERK1/2 upregulation for a prolonged period.203 Moreover, the endogenous opioid peptides pro-enkephalin and pro-orphanin were shown to mediate oxidative stress by ERK phosphorylation and subsequent CREB activation through a mitogen- and stress-activated kinase 1 (MSK1)–dependent process in astrocytic cultures.205

An extensive body of work has delineated the effects of KOR activation on neuronal ERK1/2 phosphorylation within the mesolimbic dopaminergic circuit in the context of stress. pERK1/2 is a regulator of phosphorylated cAMP response element–binding protein (pCREB), which is responsible for the nuclear transcription of BDNF and endogenous opioid peptides.206 Changes in receptor-specific ERK phosphorylation modulate the levels of proBDNF and mature (m)BDNF, which respectively facilitate long-term depression and long-term potentiation.207 KOR activation and the subsequent upregulation of CREB is a robust molecular characteristic observed following exposure to a wide variety of stressors. ERK1/2 hyperphosphorylation in PFC dendrites is a hallmark of stress; following exposure to paradigms of chronic stress and aversive conditions such as foot shock, rodents exhibited persistent increases in ERK1/2. Moreover, reduced phospho-CREB expression was determined following stress exposure across several cortical and subcortical regions.208,209 At the level of the VTA, KOR upregulation of pCREB mediated increases in BDNF and dynorphin expression in DA terminals in the NAc, promoting deficits in sucrose preference, and resulting in increased passive behaviors in the forced swim test and learned helplessness paradigms.204,206 By contrast, KOR-mediated BDNF increases in the hippocampus attenuated these behavioral effects.204 Similarly, upregulation of KOR activity in the amygdala produced timing-dependent effects on behavior in the learned helplessness paradigm, where KOR agonist pretreatment increased escape deficits to electric shock exposure, and KOR agonist administration post-testing reversed this effect.206

Overall, these data demonstrate that opioid compounds, when administered acutely, modulate ERK1/2 in a manner like that of chronic treatment with slower-acting antidepressants and that they have the acute effects of rapid-acting, novel therapeutics.

BDNF, TrkB and eEF2 Phosphorylation

Ketamine infusion promotes rapid release of BDNF. The release of this highly potent neurotrophin (Figure 1) subsequently activates its receptor TrkB and induces a cascade of signaling events, including ERK1/2 phosphorylation, that ultimately leads to the inhibition of eukaryotic elongation factor 2 kinase (eEF2K), a Ca2+/calmodulin-dependent serine/threonine kinase that phosphorylates eEF2, which is responsible for the rapid protein translation required to produce the antidepressant effects associated with ketamine-induced changes in neuronal plasticity.150,210,211 Importantly, stress-induced BDNF deficits were restored following acute administration of rapid-acting compounds such as ketamine, and following chronic, but not acute, administration with antidepressants.194,199,207,212

Intracerebroventricular (ICV) administration of the endogenous opioids leu- and met-enkephalin has been shown to robustly upregulate BDNF levels in the hippocampus of rats.213 Moreover, systemic and ICV administration of the DOR agonists BW373486 and DPDPE, respectively, also elevated BDNF levels in the frontal cortex, hippocampus, and amygdala of mice within three hours of administration.214,215 By contrast, bupropion and desipramine did not modulate BDNF levels three hours post-injection.214 Interestingly, this study reported tolerance to the effects of BW373486 on BDNF levels in the hippocampus and amygdala but not in the frontal cortex, which continued to exhibit DOR agonist–induced elevations in BDNF expression.214 In addition, mice treated chronically with the KOR agonist U50,488 exhibited robust reductions in BDNF protein expression in the frontal cortex and hippocampus.216 While the KOR antagonist nor-BNI blocked the effects of chronic KOR activation in both regions, chronic imipramine, but not fluoxetine or citalopram, administration blocked KOR-induced reductions in BDNF in the frontal cortex; BDNF reductions in the hippocampus recovered only following chronic citalopram treatment.216 These findings are in agreement with an earlier study that demonstrated the ability of nor-BNI to augment BDNF levels in the hippocampus following ICV administration one day post-administration.217 Interestingly, the nor-BNI–induced elevation in BDNF was not evident when tested on days 3 to 14 post-administration in these stress-naive mice.217 This finding is reminiscent of the tolerance exhibited following DOR agonist treatment on hippocampal BDNF. It would be valuable to consider whether BDNF changes are sustained in the frontal cortex following KOR antagonist treatment.

Less is known about the impact of NOP antagonists on BDNF levels, although one report indicated that administration of UFP101, which reversed the effects of chronic unpredictable stress in rats, did not alter BDNF levels in the hippocampus.218 No other region was explored in that study. Moreover, despite the extensive literature detailing the impact of MORs on BDNF and glutamatergic plasticity in the context of hyperalgesic priming and the establishment of drug-seeking behaviors, little information exists pertaining to the effects of MOR agonists and antagonists on BDNF levels in the hippocampus and frontal cortex in the context of stress exposure.219,220

Overall, these data suggest that DOR agonists and KOR antagonists can positively modulate BDNF levels in a time frame that reflects that of the rapid action of ketamine. Continued and more extensive exploration of this potential mechanism is warranted for the compounds currently under clinical consideration for treating MDD.

CONCLUSION

There is a great deal of optimism in establishing opioid-based compounds as viable therapeutics for MDD and other stress-related disorders. Clinical evidence suggests that such opioid-based therapeutics exert beneficial effects rapidly and that they target symptoms of MDD that were previously refractory to current antidepressant medications, including cognitive impairment and suicidal ideation. At a mechanistic level, because opioid signaling stimulates cellular processes and neural circuitry involved in facilitating stress adaptation and resilience, the normalization of aberrant opioidergic tone may recapitulate the rapid ability of ketamine to reestablish normal neuronal function and reverse depressive behaviors.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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Keywords:

delta opioid receptor (DOR); kappa opioid receptor (KOR); major depressive disorder; mu opioid receptor (MOR); nociceptin/orphanin FQ receptor (NOP)

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