Advances in Pharmacological Treatments for Depression: Novel Mechanisms and Clinical Applications

Recent clinical reports have described encouraging results on several receptor targets for the pharmacological treatment of depression. [Vasiliu 2022a]; [Vasiliu 2022b] For some of these prototype compounds, these initial results will hopefully provide a foundation for second or third-generation analogues with potent efficacy and more tolerable safety profiles.

Opioid Receptors

• The opioid system plays a vital role in pain processing, stress responses, immune functioning, and respiration; dysfunction in this system is associated with anhedonia and poor mood control. However, targeting this system presents notable challenges due to their involvement in the reward system (i.e., they have substantial abuse potential). [Morgan and Christie 2011]
• Buprenorphine is a partial mu-opioid receptor (MOR) agonist, and a delta and kappa opioid receptor (DOR and KOR, respectively) antagonist approved as an analgesic but has also been shown to reduce depressive symptoms and anxiety behaviours. [Yovell et al 2016]; [Serafini et al 2018]

Peroxisome Proliferator-Activated Receptors (PPARs)

• PPARs are transcriptional factors that regulate energy homeostasis, lipid metabolism, and glucose regulation. [Mirza et al. 2019]
• Modulation of the PPAR gamma system is postulated to be a novel therapeutic target after reduced activity levels were linked to central and peripheral inflammation that was then suggested to contribute to cognitive and affective manifestations. [Gold et al. 2013]
• Of note, the SNRI venlafaxine requires PPAR activation to induce its antidepressant effects [Chen et al. 2019], while the PPAR-γ agonist pioglitazone normalises the stress response and reduces depressive behaviours in animal models. [Beheshti et al 2021]; [Lam et al 2021]

Metabotropic Glutamate Receptors (mGluRs)

• These G protein-coupled receptors have several subtypes, some of which have been shown to have antidepressant-targeting potential. For example, the abnormal upregulation of mGluR 2/3 expression in hippocampal neurons has been associated with learned helplessness and stress-induced anhedonia. [Liu et al. 2020]
• Selective mGluR 2/3 antagonists and negative allosteric modulators (NAMs) potentiate glutamate neurotransmission and confer antidepressant efficacy. [Joffe et al. 2020]; [Pałucha-Poniewiera et al. 2021]
• More recently, the blockade of mGluR 2/3 with the orally available prodrug TP0473292 (the active ingredient in TS-161) was shown to have ketamine-like antidepressant effects. [Watanabe et al 2022]
• Currently, a phase 2 clinical trial in patients with TRD is recruiting [NCT04821271].

NMDA Receptors: 

• Impaired neural plasticity is postulated in the development of major depressive disorder (MDD) through dysregulated glutamatergic signalling via N-methyl-D-aspartate receptors (NMDARs).
• Notable NMDAR antagonists with therapeutic potential include esketamine, ketamine, dextromethorphan, and memantine.
• According to the NMDA hypothesis of depression, increased calcium influx through NR1-2D channels inhibits synaptic protein production and availability, impairing neural plasticity.

Esmethadone: 

Uncompetitive NMDAR antagonists, such as Esmethadone (REL-1017), can potentially restore synaptic protein levels and physiological synaptic plasticity by blocking excessive tonic calcium currents.

Esmethadone administration has been found to increase synaptic protein levels in the medial prefrontal cortex (mPFC) but not in the hippocampus.

Esmethadone’s efficacy and safety may be influenced by its selectivity for tonically hyperactive NR1-2D subtypes and its favourable pharmacokinetic profile, allowing once-daily oral administration.

Clinical trials have demonstrated the efficacy of esmethadone as an adjunctive treatment for major depressive disorder. One week of treatment with d-methadone (esmethadone) studied in a placebo-controlled, double-blind, randomised inpatient clinical trial of treatment-resistant patients with major depression exhibited clear efficacy at day 4, 7, and 14 (7 days after the last dose). [Fava et al., 2022]

Ketamine and Esketamine: 

Read the detailed pharmacology of ketamine and esketamine.

The proposed mechanism of action for ketamine and esketamine in depression is the “disinhibition hypothesis”.

The selective antagonism of NMDARs on GABAergic inhibitory interneurons leads to a reduction in overall inhibition, thereby promoting increased excitatory synaptic transmission in the medial prefrontal cortex (mPFC) and facilitating the restoration of synaptic proteins via a mechanism dependent on brain-derived neurotrophic factor (BDNF).

Ketamine and its enantiomers are commonly administered intravenously or intranasally due to inconsistent oral absorption. However, caution is warranted as these medications have a narrow safety margin, with approximately 70% of patients experiencing dissociative symptoms when used at current dosages for depression treatment.

Of particular concern is the neurotoxicity previously observed in rat models following acute exposure to high doses of ketamine, broadly referred to as ‘Olney’s lesions’. This type of toxicity presents as abnormal neuronal cellular vacuolisation, followed by neuronal death and has been associated with ketamine’s inhibition of the N-methyl-d-aspartate receptor (NMDAR). [Morris et al., 2021]

In comparison, long-term use of esmethadone may be safer than other NMDAR antagonists associated with the development of lesions.

Dextromethorphan–Bupropion (Auvelity):

The combination dextromethorphan–the FDA recently approved bupropion (Auvelity) for treating major depressive disorder in adults. It is the first rapid-acting oral medication to demonstrate statistically significant antidepressant efficacy compared to a placebo within one week. [Khabir et al., 2022]

Dextromethorphan acts as a noncompetitive NMDA receptor antagonist and exhibits agonistic effects on mu-opioid and sigma-1 receptors.

With an approximately threefold higher affinity for the NMDA receptor than esmethadone, dextromethorphan also influences cellular calcium homeostasis, excitotoxicity, endoplasmic reticulum (ER) stress, and mitochondrial function through sigma-1 receptor activation. Its antidepressant properties extend to serotonin transporter, calcium channels, muscarinic sites, beta and alpha-2 receptors, and 5HT-1B/D receptors.

Since dextromethorphan is quickly metabolised by cytochrome P450 2D6(CYP2D6), it isn’t easy to achieve therapeutic levels of dextromethorphan using the oral route.

When combined with bupropion, a CYP2D6 inhibitor that enhances dextromethorphan plasma concentrations, Auvelity (dextromethorphan 45 mg and bupropion 105 mg) demonstrates rapid and significant improvement in depressive symptoms compared to bupropion alone. [Tabuteau et al, 2022]

This combination therapy offers a comprehensive approach to treating depression by modulating norepinephrine, dopamine, glutamate, and serotonin levels. Auvelity capitalises on the mechanisms of action seen in multiple antidepressant medications, providing a consolidated treatment option.

While the dextromethorphan-bupropion combination demonstrates better tolerability compared to ketamine and esketamine, it is important to consider the potential side effects associated with the simultaneous use of two distinct drugs.

This consideration becomes particularly relevant when prescribing the combination drug to patients already taking other medications, as it introduces the complexities of polypharmacy.

Galanin Receptors

Galanin is a neuropeptide that can bind to three different galanin receptors (GALR): activation of GALR1 or GALR3 induces depressive-like behaviours in animal models, whilst activation of GALR2, in contrast, mediates an antidepressant effect. [Morais et al. 2016]

We covered galanin in the neuropsychiatry of sleep. 

This observation is supported by early research into the antidepressant fluoxetine, which showed that it upregulated GALR2 expression in the dorsal raphe nucleus. [Lu et al. 2005]

Combination therapy with antidepressants such as fluoxetine is suggested to have synergistic potential, with early preclinical results showing that the co-administration of fluoxetine with GAL(1-15), an N-terminal fragment of galanin, reduced behaviours likened to despair and anhedonia. [Flores-Burgess et al. 2022]

Inflammation

Multiple lines of bidirectional evidence link inflammation with depression with implications for aberrant cytokine production and the crossing of pro-inflammatory cytokines across the blood-brain barrier via humoral, cellular, and neural pathways. [Miller et al 2009]; [Köhler et al 2017]; [Syed et al 2018]

There is compelling evidence indicating the presence of an inflammatory phenotype in depression. Elevated levels of peripheral C-reactive protein (CRP) exceeding 3 mg/l have been associated with a specific depressive phenotype characterized by symptoms resembling “sickness behaviour,” including anhedonia, apathy, decreased appetite, fatigue, sleepiness, pain, suicidality, and cognitive impairments. These symptoms are observed across various disorders, suggesting that neuroinflammation may contribute to the shared features among neuropsychiatric conditions. [Maes et al., 2012]

Neuroinflammation and Depression – A Simplified Guide

• Anti-inflammatory treatments such as cyclooxygenase (COX) 2 inhibitors block the synthesis of proinflammatory prostaglandins.
• For almost two decades [Müller et al. 2006] have been studied to determine how closely associated inflammation is with depression.
• In one meta-analysis, adjunctive celecoxib resulted in better remission and response rates than placebo in patients with MDD. [Na et al. 2014]
• Augmentation with Minocycline, a tetracycline antibiotic with anti-inflammatory and GABA-modulating effects, showed a significant treatment in patients with depression who had elevated CRP levels of more than 3 mg/L with a CRP threshold to distinguish responders from non-responders of 2·8 mg/L. [Nettis et al., 2021]
• More recently, Stachowicz and colleagues showed that co-administration of a COX-2 inhibitor with a mGluR5 antagonist suppressed glial activation and modulated oxidative stress mechanisms in an animal model of depression. [Stachowicz et al 2021]

It was postulated that the involvement of oxidative stress mechanisms was possibly related to regulating excitatory amino acid transporters (EAATs) via the interaction between COX-2 and mGluR5.

Bai and colleagues did a systematic review and meta-analysis of the efficacy and safety of anti-inflammatory agents for the treatment of MDD with a total sample of 1610 participants. [Bai et al., 2020]

Overall, treatments, including celecoxib (a cyclooxygenase-2 inhibitor) and other non-steroidal anti-inflammatory agents, omega-3 fatty acids, and statins had a beneficial effect with a reduction in depressive symptoms in monotherapy or as an adjunct to antidepressant medication.

Is There a Role for Statin Therapy in Psychiatry? – Professor Michael Berk

Oxidative and Inflammatory Biomarkers As Targets For Novel Therapies – Prof Michael Berk

Dopaminergic agents in inflammatory depression

Levodopa: [Bekhbat et al., 2022]

• In depressed individuals with elevated C-reactive protein (CRP) levels, the administration of levodopa effectively reversed the impact of inflammation on the brain’s functional connectivity within the reward circuitry, reducing anhedonia.
• Levodopa exhibited enhanced functional connectivity between the ventral striatum and ventromedial prefrontal cortex reward circuit, specifically in patients with higher CRP levels (> 2mg/L).
• The observed enhancement of reward circuitry connectivity in depressed individuals with elevated CRP levels following levodopa treatment was also associated with a decrease in anhedonia symptoms.

SSRIs vs Dopaminergic Agents: 

• IFN-alpha-induced fatigue and psychomotor retardation are less responsive to SSRI therapy, and neurotransmitter systems other than serotonin, such as dopamine, may be involved in these SSRI-resistant, inflammation-related symptoms. [Felger & Miller, 2012]
• Treatment-resistant depression often involves deficits in interest, motivation, and hedonic capacity. While antidepressants targeting norepinephrine and serotonin may yield poor outcomes for these symptoms, an intact dopamine system is believed to be crucial for addressing them. [Felger & Miller, 2012]
• The largest meta-analysis of 45 studies representing 1517 MDD patients revealed that antidepressant treatment significantly decreases peripheral levels of IL-6, TNF, IL-10, and CCL2, but these were not associated with treatment response. [Köhler et al., 2018]
• In individuals with elevated baseline levels of IL-17A, the combination therapy of Bupropion and SSRI demonstrated a more significant reduction in treatment severity. IL-17A is known to disrupt the blood-brain barrier and impact dopamine synthesis. Conversely, dopamine has been found to suppress the Th17 cell-mediated immune response. [Jha et al., 2017]
• In another study, patients with low levels of CRP (<1 mg/L) showed greater improvement with Escitalopram than with nortriptyline. However, improvement was greater with nortriptyline than with Escitalopram for patients with higher CRP levels. [Uher et al., 2014]

Hypothalamic-Pituitary-Adrenal Axis

Stress-induced depression has been linked to genetic variants of the mineralocorticoid receptor (MR), which can enhance susceptibility or promote resilience to life’s stressors and the risk of developing MDD. [Joëls and de Kloet 2017]

Stress downregulates MR expression, whereas antidepressants can actually increase MR expression; this increased MR activity reduces HPA axis activity, thus promoting stress-coping mechanisms. [de Kloet et al 2016]

Neurobiology of Stress and Resilience

• MR and glucocorticoid receptors (GRs) are a dual-receptor system with differing affinities for glucocorticoids as well as different locations within the brain, with MR found predominantly in the limbic system and cortical areas, whereas GRs are spread throughout.
• MR and GR cooperate in glucocorticoid regulation; however, the MR: GR ratio is crucial from a temporal and contextual perspective when considering their role in providing negative feedback regulation of the HPA axis. [de Kloet et al 2018]; [Joëls et al 2018]
• The dexamethasone suppression test (DST) evaluates HPA axis activity in depression. Melancholic depression patients may show a lack of suppression in ACTH and cortisol levels when given low-dose dexamethasone, indicating HPA axis dysfunction. Elevated urinary free cortisol levels and a 70% sensitivity of DST assist in identifying HPA axis hyperactivity in severe cases of melancholic depression. [Hassamal, 2023]
• Barroca and colleagues recently showed that prednisone and dexamethasone (GR agonists) lowered cortisol levels in patients with MDD that had experienced early-life stress. These results are suggestive of GR regulators as novel therapeutics for MDD. [Barroca et al, 2020]

While glucocorticoid receptor (GR) antagonists and agents that inhibit cortisol synthesis have been developed, their efficacy has been hindered by the presence of phenotypic and genotypic diagnostic heterogeneities.

Recent research has shifted focus towards arginine-vasopressin (AVP) and the vasopressin V1B receptor (V1BR) as key factors contributing to HPA axis dysregulation. The binding of AVP to the V1BR stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland, leading to the secretion of cortisol. Several studies have observed increased levels of AVP in the plasma and brain nuclei of depressed patients, indicating the dysregulation of the HPA axis through AVP-V1BR overactivity. [Hassamal, 2023]

Gut Microbiota

Finally, the gut microbiome’s influence on the HPA axis has been explored in recent years through the analysis of microbial metabolites that can act as neurotransmitters. [Sirisinha 2016] Here, dysbiosis is frequently linked to various non-communicable diseases as well as the development of allergies, inflammatory diseases, and various neurological disorders.

Gut Microbiome (Gut-Brain Axis) and Depression – Pathophysiology | Role of Pre and Probiotics

• Kosuge et al. showed that Bifidobacterium breve improved depressive symptoms in a mouse model of chronic social defeat stress via modulation of the gut microbiota composition and suppression of IL-1β in the prefrontal cortex and hippocampus. [Kosuge et al., 2021]
• A meta-analysis by Ng and colleagues pooled data from 10 clinical trials that studied the impact of probiotic supplementation on depressive symptoms. Although no significant difference was reported, subgroup analysis found substantial improvements when only patients with mild-to-moderate depression were included. [Ng et al., 2018].
• In a randomised clinical trial, 49 adults with major depressive disorder and an incomplete response to antidepressants were assigned to either a multistrain probiotic supplement or a placebo for eight weeks. The probiotic group, which received a supplement containing 14 beneficial bacteria strains, exhibited greater symptom improvement compared to the placebo group, starting from the fourth week. This study indicates that adding a multistrain probiotic as an adjunctive treatment could be beneficial for patients with depression who do not fully respond to antidepressant medication. [Nikolova et al., 2023]
• A recent meta-analysis found that prebiotics, probiotics, and synbiotics led to notable improvements in depression symptoms compared to the placebo group, with probiotics showing particularly significant antidepressant effects. The treatment was effective for both mild and moderate depression, and studies with a higher proportion of male participants reported stronger effects in alleviating depressive symptoms, suggesting that manipulating gut microbiota may be beneficial for mild-to-moderate depression in clinical practice. [Zhang, 2023]

As such, the potential mechanisms between the microbiota-gut-brain axis and depression suggest that functional food, psychobiotics, and engineered bacteria should be considered when researching a comprehensive antidepressant therapeutic regimen. [Schnorr et al 2016]; [Bambling et al 2017]; [Luhavaya et al 2019]

In conclusion, the field of pharmacological treatments for depression is witnessing exciting advancements as researchers explore novel pathways and receptors.

The inclusion of NMDA receptors, opioid receptors, galanin receptors, and the exploration of inflammation, the gut-brain axis, and the HPA axis offer promising avenues for developing innovative therapeutic interventions.

These developments are grounded in a deepening understanding of the neuroscientific basis of depression and hold the potential to revolutionize the treatment landscape.

By targeting specific neurochemical pathways and leveraging mechanistic knowledge, researchers strive to develop medications with rapid onset of action, improved tolerability, and increased efficacy.

Furthermore, identifying novel receptors and pathways opens doors for tailored treatments, addressing the needs of individuals with difficult-to-treat depression. As the scientific and clinical communities continue to advance their understanding and conduct specific trials, there is hope these developments will bring about improved treatments, offering renewed hope to individuals affected by depression worldwide.