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: