Opioid agents for treatment-resistant depression





Introduction


Almost 70% of depressed individuals do not adequately respond to common antidepressants and need multiple therapeutic trials in order to achieve a full remission. Furthermore, according to the STAR*D study, patients who need more trials had the greatest risk of failure ( ). This subgroup of subjects experiencing TRD is more likely to suffer from recurrent episodes and shows a higher risk to manifest substance abuse and/or suicidal behavior as well as more severe psychosocial impairment and physical disability when compared to individuals with major depressive disorder (MDD) ( ; ).


Treatment resistance may occur in patients previously responsive to treatments or gradually as a neuroprogressive condition ( ), characterized by more severe recurrent episodes with a worse response to treatments and residual symptoms recognized as an index of poor outcome ( ).


Treatment strategies commonly involve antidepressant combinations, augmentation, or switching, but the use of nonpharmacological options such as vagus nerve stimulation, transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT) has been also described although linked to complications such as the increased risk of toxicity due to pharmacological combination regimens or higher drug dosages, memory impairments with ECT, and others ( ).


The difficulty in adequately treating TRD presumably reflects the multiple neurobiological mechanisms underlying its clinical presentation. As a matter of fact, monoamine depletion theories are able to explain TRD only partially; therefore, in recent years, studies focused on different mechanisms including cortisol levels, Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines, and new medications have been stressed. Importantly, existing research highlighted the importance of endogenous opioid system and its abnormalities in regulating mood, and thus playing a crucial role in affective disorders. These findings suggested that it may be possible to use drugs targeting this system for people with TRD ( ).


It would be more correct to say that we should return to investigate the potential of drugs capable of acting on the opioid system, given the ancient use of the plant Papaver somniferum to improve mood dates back to the Sumerian age (3000 BCE). In addition, in the 19th century, opium, first introduced by a German psychiatrist, was known as one of the psychoactive medications used to treat melancholic states with agitation. Later, even Emil Kraepelin recommended opium tincture to treat dysphoria and agitated depression ( ). However, the use of these remedies commonly resulted in abuse and addiction; therefore, with the introduction of the monoamine oxidase inhibitors (MAOIs) in the 1950s, tricyclics (TCAs) in the 1960s, and SSRIs in the 1980s, the therapeutic potential of opioid derivatives for mood disorders has been long neglected ( ). Many compounds are now being studied with renewed interest for their potential benefit for depressed patients, including those with TRD.


Opioid agents and their potential in treatment-resistant depression


Various studies reported that the opioid system is involved in the modulation of pain, response to stress, reward (and therefore addiction), respiratory functioning, control of gastrointestinal motility, and immune and endocrine systems regulation—in particular, at the level of the hypothalamic-pituitary-adrenal (HPA) axis ( ). The opioid system is partially regulated by three different receptors, μ-, δ-, and κ- (these receptors are coupled to G proteins that commonly bind a family of three opioid peptides, i.e., β-endorphin, enkephalins, and dynorphins), which are disseminated in the central and peripheral nervous systems ( ). Μ-opioid receptors (MORs), when activated, convey an analgesic effect but they are also involved in the modulation of behaviors which are crucial in the conservation of the human species, such as eating, reproduction and response to social stimuli ( ). Δ-opioid receptors (DORs) and κ-opioid receptors (KORs) modulate pain, but they also seem to play a role in depression: encephalin/DORs have a mood-enhancing activity while dynorphin/KORs—acting on dopaminergic neurons in nucleus accumbens—appear to be related to depressive-like behaviors ( ; ). Moreover, stress may lead to increased levels of dynorphins that bind to KORs, thus inducing symptoms like dysphoria and anhedonia ( ). Opioid receptors are highly expressed in cortical regions involved in the response to stressors and in the regulation of emotionally salient stimuli as well as subcortical limbic and paralimbic circuits that process stressful stimuli, reward, hedonic response, and mood control ( ; ).


As mentioned above, opioid receptors modulate important neurotransmitter systems that are related to major depression, such as the dopaminergic (DA), serotonergic (5-HT), and noradrenergic (NA) systems at multiple sites; synaptic plasticity and neurogenesis in the hippocampus; functioning of the hypothalamic-pituitary-adrenal gland (HPA) axis, a major neuroendocrine stress system, and regulation of BDNF activity ( ). Importantly, 50% of MDD patients experience cognitive dysfunctions in one or more cognitive domains (such as memory, attention, executive functions and processing speed), and cognitive impairment is a significant contributor (mediator or moderator) of functional impairment in MDD; thus, medications with the potential to target cognitive impairment may be useful in TRD. Cognitive deficits tend to be more frequent and pronounced in patients with TRD, and often do not improve with the remission of affective symptoms ( ). Although conventional antidepressants attenuate depression severity, they are linked to mixed outcomes in terms of long-term cognitive dysfunctions. In the context of mood, opioid antagonists may be useful for improving psychomotor responses, decision making, and attention; in addition, they may effectively target cognitive dysfunctions presumably by modulating DA neurotransmission within the mesolimbic circuit and specific cortical regions ( ).


It is generally accepted that the opioid system may be dysregulated in depression ( ). Further evidence to this regard are provided by postmortem studies, highlighting the existence of endorphin deficiencies coupled with an increased density of μ-receptors in the brains of depressed patients who committed suicide ( ; ). Moreover, from a clinical point of view, both traditional antidepressants and ECT indirectly modulate opioid neurotransmission ( ), and drugs that act as MOR agonists demonstrated a rapid mood improvement in patients with MDD or TRD ( ).


Opioid agents: Mechanisms of action, pharmacokinetics and clinical studies


Among the opioidergic drugs that may be involved in the treatment of affective disorders, the following medications are currently used as pain-killers or in the setting of opioid addiction: methadone , buprenorphine , tramadol and naltrexone . Tianeptine, an atypical agonist of the μ-opioid receptors with clinically negligible effects on the δ- and κ-opioid receptors, has antidepressant and anxiolytic effects with a relative lack of sedative, anticholinergic, and cardiovascular adverse effects, and it has potential uses for treating anxiety, asthma, and irritable bowel syndrome. However, there are also new treatments under investigation which have been developed to treat major depression such as ALKS-5461 (buprenorphine plus the μ-antagonist, samidorphan) and m-trifluoromethyl-diphenyl diselenide and Salvindolin—the latter having been tested only in preclinical models.


Below, the most relevant opioid agents used in TRD are summarized:


Methadone


Mechanism of action: Methadone is a diphenylpropylamine derivative. It is an agonist of MORs, and to a lesser extent KORs, but it may also bind to the N -methyl- d -aspartate receptor (NMDAR) where it acts as an antagonist ( ). Methadone also acts as a serotonergic drug, being able to inhibit the serotonin transporter SERT ( ); this latter mechanism of action should be taken into account particularly when coprescribing other serotonergic drugs, such as MAOIs due to the risk of serotonin toxicity. Another mechanism of action that seems to be involved in the antidepressant effect of methadone is the saturation of upregulated endorphin receptors (due to lower endorphin levels in depressed subjects). This may stimulate dopamine neurons to release dopamine in order to restore hedonic tone, thus improving depressive symptoms ( ). It should also be noted that methadone has been shown to reduce cortisol levels immediately after its administration: in a study which was conducted in 1982 by Judd and colleagues, intramuscular administration of 10 mg of methadone resulted in a rapid reduction of cortisol levels and significant reduction of manic symptoms ( ). As such, methadone may be potentially used either in unipolar and bipolar depression (in the latter case, the previously mentioned use of opiates by Emil Kraepelin for agitated depression is of particular interest).


Pharmacokinetics: Methadone is generally orally administered, has a high fat solubility, is metabolized by cytochrome P450 (CYP) 3A4, CYP2D6, and CYP2B6. The metabolites resulting from N -demethylation (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP)) are inactive and may be measured in urine (this may be useful for monitoring purposes). The excretion of methadone after biotransformation commonly occurs via renal and fecal elimination; the terminal half-life ranges between 8 and 59 h, with a significant degree of individual variability due to genetic differences regarding cytochromes related to methadone metabolism ( ).


Clinical studies: Methadone’s antidepressant action has been investigated mostly in opioid-dependent patients with comorbid MDD. For instance, Dyer and colleagues found that the antidepressant effect of methadone appears to be directly related to its circulating levels: the complete resolution of clinical symptoms is commonly achieved within 3 h while the effect diminishes as methadone levels decline ( ). In another study, Dean et al. compared a cohort of patients who were treated with methadone + placebo with another cohort who was prescribed methadone + fluoxetine and found a significant improvement of depressive symptoms in both groups; in addition, the antidepressant effect did not increase when adding a serotonergic drug ( ). In another study, the same authors demonstrated a rapid improvement in depressive symptoms over several weeks in a group of 30 patients who were treated with methadone as well as in a control group (24 patients) who were treated with buprenorphine ( ). Importantly, patients in methadone maintenance treatment who present with comorbid MDD generally require a 20%–50% higher dosage of this medication ( ). Regarding methadone daily dosage, patients with comorbid substance abuse/dependence disorder need higher dosages (70–150 mg per day vs. 30–40 mg per day in patients without comorbidity) in order to obtain a better treatment retention and stabilize their clinical symptoms ( ).


Efficacy for treatment-resistant depression: Unfortunately, studies on the antidepressive activity of methadone in TRD are very limited due to the occurrence of adverse effects related to the possibility of overdose. This factor may limit the potential utility of methadone for TRD patients. Further studies are needed to this specific regard.


Adverse effects and toxicology: Methadone has, unfortunately, a potential lethality risk related to overdose, which may result from respiratory depression/pulmonary edema or ab-ingestis pneumonia. Respiratory depression is unlikely with methadone mono-therapy, especially if the patient has developed tolerance; however, the risk of respiratory depression may be increased when methadone is coadministered with drugs inhibiting CYP3A4 (e.g., fluoxetine, fluvoxamine, ketoconazole, erythromycin) ( ). Another interaction causing toxicity is with MAOIs or other antidepressant medications which, when administered together with methadone, may cause an increase in the risk of serotonin toxicity ( ). Methadone may be also responsible for cardiac arrhythmias and cardiovascular collapse ( ). Common but less-dangerous adverse effects include sedation, gastrointestinal discomfort, constipation, and nausea ( ). The risk of withdrawal from methadone can be increased when it is prescribed concomitantly with opioid antagonists (e.g., naltrexone) or inducers of CYP3A4 (e.g., carbamazepine, rifampicin, fluconazole) ( ). Finally, an uncommon long-term adverse effect of methadone is an endocrinopathy known as the opioid-induced androgen deficiency (OPIAD), which may cause hypogonadism and hypotestosteronism due to an alteration of the hypothalamic-pituitary-gonadal/adrenal axis ( ).


Buprenorphine


Mechanism of action: Buprenorphine is a partial μ-agonist and δ −/κ-antagonist. KOR antagonism seems to be implicated in the antidepressant effect of this drug, especially in reducing anhedonia ( ). Others have suggested that the importance of MOR agonism action of buprenorphine is important in the setting of TRD, as demonstrated in animal models of depressive behavior (e.g., the learned helplessness model), where morphine or other μ(mu)-opioid peptide (MOP) agonists showed an antidepressant-like activity which can be antagonized by naloxone ( ). Moreover, based on its partial agonist properties, buprenorphine presents a lower risk of respiratory depression in overdose (when not associated with other Central Nervous System (CNS) depressants such as alcohol and benzodiazepines). Buprenorphine commonly acts as an exogenous endorphin but, similar to methadone, it also acts as an NMDA antagonist ( ).


Pharmacokinetics: Buprenorphine is a semisynthetic derivative of thebaine, which has been isolated from opium poppy ( ). Buprenorphine is usually administered sublingually. It’s a lipophilic molecule and, once in circulation, it is 96% bound to plasma proteins ( ). The elimination half-life of buprenorphine is about 20 h. Buprenorphine undergoes hepatic metabolism and is transformed into norbuprenorphine through N-dealkylation by CYP3A4 and CYP3A5. Since buprenorphine is metabolized by CYP3A4, caution should be used when it is prescribed with CYP3A4 inducers or inhibitors. Norbuprenorphine, an active metabolite that possesses a MOR agonist and partial KOR agonism action, is then conjugated with glucuronic acid and eliminated mostly through feces and, to a lesser extent, by urine ( ).


Clinical studies: Due in part to potentially advantageous safety profiles, buprenorphine (together with ALKS-5461) are among the most investigated opioids in the treatment of depression. There are at least 15 studies both in patients with addiction ( ; ; ; ; ; ) as well as in drug-naive patients with MDD or TRD ( ; ; ; ), as well as borderline personality disorder ( ) and posttraumatic stress disorder (PTSD) ( ). Other studies investigated the efficacy of buprenorphine specifically for reducing suicidal ideation or nonsuicidal self-injury ( ; ; ; ; ). For further details, please see Table 16.1 .



Table 16.1

Summary of the most relevant studies concerning buprenorphine and depression or suicidal behavior.




































































































































































Reference Study design Psychiatric condition Sample Treatment Study duration Psychometric instruments Main conclusions Limitations/shortcomings
Double-blind, placebo-controlled clinical trial MDD 10 adults 0.2 mg sublingual BUP 5–8 days HAM-D; IMPS; VBS Four patients showed more than 50% reduction in depression, two a moderate response, and four a slight reduction Short duration. Lack of a control group. The small sample size does not allow the generalization of the main findings.
Single-blind, placebo controlled clinical trial Nine subjects had borderline personality disorder, six had not specified disorders 15 adults 15 patients: sublingual BUP starting at 0.2 mg till 12.3 mg 1 month HAM-D Nine out of the fifteen patients showed 30%–50% reduction on HAM-D. These nine patients met the diagnostic criteria for Borderline personality disorder while the others had different diagnosis Short duration. The small sample size does not allow the generalization of the main findings. The diagnostic heterogeneity with a lack of a precise description of all diagnoses and group characteristics.
Observational prospective study Opioid addiction 40 adults (mean age 30.7 years; 31 M and 38 F) Sublingual BUP mean dose 3.2 mg (range from 2 to 8 mg) 1 month BDI; SDS Significant mood improvement since the end of the first week, that continues over the second week. Depressive symptoms steadily declined during the month Short duration. Lack of control group. The small sample size of the study. Diagnostic heterogeneity. Depression was not included as a primary outcome. Self-report measures.
Placebo controlled clinical trial Veterans with previous substance abuse and multiple diagnoses (PTSD, MDD, Panic Disorder, Bipolar Depression, Borderline, Schizophrenia, Adjustment Disorder), plus a normal subject 12 adults (age from 37 to 52 years; all M) Sublingual BUP 0.3 mg or placebo. Four subjects in open tests and eight subjects in double blind test 6 h POMS Nine patients responded with a relief in anxiety, depression and hostility Short duration. Groups receiving placebo or drug were not described in detail. The small sample size does not allow the generalization of the main results. Diagnostic heterogeneity. Lack of exclusion criteria. A part from POMS, lack of standardized measures.
Open label clinical study TRD Ten adults (3 completed 4 weeks and 4 completed 6 weeks, 3 dropped-out; of 7 who completed at least 4 weeks the mean age was 44 years), four were M and three F Intranasal or sublingual BUP starting at 0.15 mg and titrated until a maximum of 1.8 mg (final average dose was 1.26 mg) 6 weeks HAM-D; ADDS; POMS Six of seven patients achieved marked clinical improvement by the end of 1 week. This improvement in all the indicated parameters remained stable until the end of the trial Short duration. Lack of control group and placebo group. The small sample size.
Randomized, double-blind, placebo controlled clinical trial Opioid addiction Overall, 147 adults (mean age 29.5 years, 91 M and 56 F) 68 patients: 4 mg sublingual BUP and placebo methadone syrup. 79 patients: 30 mg methadone syrup and placebo BUP tablet. The therapies were started with the dosage indicated above and then individually titrated 3 months BDI Depressive symptoms improved in all subjects, with no difference between methadone and buprenorphine groups Diagnostic heterogeneity. Depression was not a primary outcome. Self-report measures. Lack of a baseline psychiatric evaluation. Lack of specified exclusion criteria.
Controlled observational prospective study Opioid addiction Overall, 60 adults (mean age 31.5 years; 45 M and 15 F) 30 patients: NAL (50 mg). 30 patients: sublingual BUP 4 mg + NAL 50 mg 3 months SCL-90; VAS for craving Despite both groups showed a significant decrease in the scores of irritability, depression, tiredness and psychosomatic symptoms, the BUP/NAL group presented a major improvement Lack of randomization and placebo control group. Diagnostic heterogeneity. Lack of baseline psychiatric evaluation. Depression was not a primary outcome. Lack of exclusion criteria. Self-report measures.
Observational prospective study TRD Six adults (mean age 45.8 years; 2 M and 4 F) Sublingual BUP ranging from 0.8 to 2.0 mg 7 days HAM-D; BDI All patients improved over the week and five of six achieved a complete remission Short duration. Lack of a control group. The small sample size. Lack of exclusion criteria.
Case-report Treatment-resistant NSSI Six adults (mean age 30.3 years; 3 M and 3 F) Personalized dose of BUP (from 0.5 mg to 6 mg) and BUP/NAL (2 mg/0.5 mg to 1 mg/0.25 mg) Different duration for each patients (from 14 days to 11 months) Five out of six patients improved their mood and NSSI behavior Short duration. Lack of a control group. The small sample size. Lack of exclusion criteria.
Case-report Chronic suicidal ideation; TRD; chronic back pain; opioid dependence One adult (61 years, F) 16 mg BUP + 4 mg naloxone 3 months The patients manifested cessation of suicidal thoughts, a decrease of pain and a reduction in depression The small sample size. Lack of a control group. Lack of exclusion criteria. Lack of standardized measures.
Open label clinical study TRD Fifteen adults (mean age 60.7 years; 7 M and 8 F) BUP titrated from 0.2 to 1.6 mg (mean dosage 0.4 mg). 13 patients used BUP as an augmentation therapy while 2 patients used BUP as a mono therapy 2 months MADRS; SSI Improvement in depression started within the first week of treatment and was sustained during the exposure to BUP. Once BUP was discontinued, MADRS score was found increased at reassessment (16th week) Short duration. The small sample size. Lack of a control group and placebo group.
Randomized, double-blind, placebo controlled clinical trial Suicidal ideation Overall, 88 adults (mean age 37.3 years, 25 M and 63 F) 57 patients: BUP (0.1 or 0.2 mg/day. Once a week, the daily dose could be raised of 0.1–0.2 mg increments until a maximal dose of 0.8 mg); 31 patients: placebo 1 month BSSI; BDI; SPS Patients in the buprenorphine group had a greater reduction in suicidal ideation, suicide likelihood and depression scores than patients in placebo group Short duration. Diagnostic heterogeneity. Self-report measures.
Case-report Chronic suicidal ideation in a substance-induced depressive disorder One adult (25 years, M) 8-mg single dose of sublingual BUP 10 days BSIS; BDI The patient had a rapid reduction and cessation of suicidal thoughts and depressive symptoms Short duration. Lack of a control group. The small sample size. Lack of exclusion criteria.
Randomized, double-blind, clinical trial Suicidal patients with opioid dependence and MDD Overall, 51 adults (mean age 32, 8 years, all M) Overall, 16 patients: 32 mg sublingual BUP. 17 patients: 64 mg sublingual BUP. 14 patients: 96 mg sublingual BUP. BUP was administered as a one-time dose. Four patients refused medication 3 days BSSI In all 3 groups a significant reduction in suicidal ideations was observed Short duration. Lack of a placebo control group. Lack of female gender in the study sample. Depression was not a primary outcome. Self-report measures.
Randomized, double-blind, placebo-controlled clinical trial Opioid dependence Overall, 61 adults (mean age 36.5 years, all M) 21 patients: placebo. 20 patients: 16 mg sublingual BUP. 20 patients: 32 mg sublingual BUP. BUP was administered as a one-time dose 4 days BSSI Suicidal ideation decreased significantly in the 32 mg BUP group. Short duration. Lack of female gender in the study sample. Depression was not a primary outcome. Self-report measures.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Oct 27, 2024 | Posted by in PSYCHIATRY | Comments Off on Opioid agents for treatment-resistant depression

Full access? Get Clinical Tree

Get Clinical Tree app for offline access