Current pharmacotherapy of depression – focused on multimodal/multifunctional antidepressants

KEYWORDS:

• Depressive disorder
• pharmacoresistance
• multimodal/multifunctional antidepressants
• pharmacogenomic tests

1. Introduction

Major depressive disorder (MDD) is a widespread disease, with a lifetime prevalence of 15% and an annual incidence of approximately 7%. It is associated with significant costs in quality of life, loss of work productivity, and a high risk of mortality. It is predicted to become the leading cause of disability in Western countries by 2030 [1].

Individual symptoms have been associated with alterations in the availability of monoamine and brain abnormalities ever since it became possible to visualize the human brain in a living person. Structural and functional alterations have been identified in brain regions involved in emotional processing (e.g. the prefrontal cortex, cingulate cortex, hippocampus, and amygdala). These regions are modulated by monoaminergic neurotransmission. It is now recognized that psychiatric symptoms correlate with malfunctioning brain circuits and that restoring neurotransmitter activity in these circuits leads to recovery. The interdependent actions of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are mediated by their cognate transporters and receptors [2].

Antidepressant (AD) drugs modify one or more monoamine systems. It has been more than 60 years since the first monoaminergic ADs emerged, and they remain the mainstay for treating depression, although some other neurotransmitters have been involved. Glutamatergic modulators such as ketamine were at the forefront of AD exploration, especially for treatment-resistant depression.

However, depression is not simply the result of neurotransmitter abnormalities. A large body of evidence implicates a dysregulated endocrine and inflammatory response system in the pathogenesis of depression. Evidence suggests that inflammation is associated with depression in certain subgroups of patients and that those who have experienced stressful life events such as childhood trauma or bereavement may be at greater risk of developing depression. Stress and depression are associated with the decreased expression of brain-derived neurotrophic factor (BDNF). BDNF is a neurotrophin playing an important role in structural integrity and neuroplasticity. Most functions of neurotrophins are mediated by the tropomyosin-receptor kinase family of tyrosine kinase receptors. ADs increase the expression of BDNF in the brain and its plasma level [3].

There is now a much better understanding of what happens with neurotransmitters after binding to a cell-surface receptor. Our knowledge goes beyond the second messenger to the third messenger (protein kinase enzyme), activating a transcription factor (the fourth messenger) capable of activating expression genes, first as RNA and then as the protein coded by the genes. These neurotransmitter-induced molecular cascades lead to the synthesis of many postsynaptic proteins important for neuron maintenance or survival. These changes provide potential new treatment targets.

AD mechanisms of action may help clinicians customize pharmacotherapy to a patient’s unique clinical profile. Individualized treatment matching therapy to specific symptom clusters may be the most effective treatment strategy to date because it targets dysfunctional brain networks and their neurotransmitters [4].

There are currently about 50 AD drugs on the market. They may be classified according to many aspects. A newer division of ADs are classified according to the number of mechanisms of action (unimodal vs. multimodal). A new classification system for psychotropic drugs according to their pharmacological domains (targets) and their modes of action was recently suggested. This nomenclature, ambitiously called ‘neuroscience-based nomenclature’ was developed to replace the current indication-based nomenclature [5].

Despite advances in pharmacotherapy, 10-15% of patients do not respond to the first treatment and an additional 30-40% have only a partial remission [6]. Treatment to remission of depression is a key to restoring full functioning and preventing relapse.

The assessment of treatment response using measurement-based assessment and rating scales is necessary in order to determine when to change the treatment strategy [7]. Patients who do not achieve remission after adequate treatment trials should be evaluated for misdiagnosis (especially unipolar vs. bipolar depression) and for treatment adequacy as well as for comorbid psychiatric and medical disorders. In a recently published study on a large sample of patients, the authors found that most subjects reached the recommended dose. However, 28% of patients had an AD trial duration of less than 4 weeks, and approximately 50% of the subjects were non-adherent. Adherence to AD treatment is not optimal [8]. In a Czech pilot study, 40% of patient with insufficient response to ADs were not within the optimal plasma level range [9]. Further, studies report that 25-42% of treated patients discontinue therapy within 1 month, and up to 72% discontinue therapy within 3 months [10].

After this evaluation, there are several therapeutic options, including changing to another AD, augmentation therapies (i.e. adding a second agent, not thought to be an AD itself), and combining ADs. The most evidence-based augmentation of specific serotonin reuptake inhibitors is augmentation with atypical antipsychotics, quetiapine, and aripiprazole, resp. brexpiprazole. Most multimodal/multifunctional ADs share with atypicals antagonism on 5-HT_2A,C receptors associated with antidepressive activity. Besides classical augmentation strategies, such as lithium and thyroid hormones, nutraceuticals have the potential to modulate several neurochemical pathways implicated in depression. Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with ADs to reduce depressive symptoms. Further, advances in technology and emerging knowledge about the dysfunctional brain circuits underlying depression and neuroplasticity have led to the development of different new neuromodulation techniques (transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation) usually used as add-on therapy. Combining ADs with different mechanisms of action influences more than one monoamine system and provides a synergistic effect, particularly for those patients who have failed on one or two drugs. There is still a surprising lack of randomized controlled trials [11].

Another treatment option is to prescribe a multimodal/multifunctional AD. Multimodal ADs have more than one mode of action, i.e. reuptake inhibition and activity on membrane-bond receptors, pooling two distinct modes of neural signaling [12]. Through these multimodal mechanisms, they produce a downstream effect on interconnected neurotransmitter systems. Multifunctional ADs have multiple actions at the same mode.

The differences among available multimodal/multifunctional ADs are based on their action at receptor subtypes, which may account for their specific effect on some difficult-to-treat symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile. Cognitive dysfunction in depression affects the ability of depressed patients to functionally recover. Vortioxetine resulted in better improvements than placebo in cognitive dysfunction in patients with MDD. Agomelatine, in addition to acting at the transporter, is a potent melatonin analog which may influence the disturbance of circadian rhythms; it may also have cytoprotective properties. The old–new AD trazodone is an example of a dose-dependent multimodal/multifunctional drug.

Monotherapy with multimodal/multifunctional ADs has some clear advantages over the combinations of ADs and augmentation. One advantage is its simplicity, associated with better compliance, and safety. Multimodal ADs may provide less adverse effects than multiple single-modality ADs. Further, unlike specific serotonin reuptake inhibitors, multimodal ADs may not decrease NE and DA transmission with clinical consequences. 5-HT systems were shown to exert a negative influence on NE and DA systems through 5-HT_2A and 5-HT_2C receptor-mediated mechanisms [13].

It may be that, if not promptly treated, MDD tends to recur and become chronic. Longer durations of untreated illness have been associated with lower treatment response/remission and more comorbidity [11]. Furthermore, the number of depressive episodes may be associated with important biological changes, including volume variations of specific brain areas (e.g. cingulate cortex and amygdala) and immunological abnormalities. It is clear that the treatment of acute depressive episodes is important, as is the prevention of recurrences in the long term.

The breakthroughs achieved in recent years in the genetics field will make it possible to change practices in diagnosing and treating patients in the near future. The research is focused on the role of genetics and epigenetics in the ethiopathogenesis of mental disorders. Genes code for proteins, proteins organize themselves into cells, and cells into neural networks. Subtle molecular abnormalities have the potential to change the efficiency of signaling, i.e. information processing [12].

Numerous studies have demonstrated an increased risk for depression and treatment response linked to genetic polymorphisms of 5HT, NE, or DA transporters and receptor subtypes. The response to drugs may be conditioned by genetic factors by more than 50% [14]. Several pharmacogenomic, commercially produced tests are now available. These tests analyze a selected patient’s genes and match this analysis to the available drugs. This procedure results in recommendations for drugs that are more likely to work for an individual patient. Application of these tests can lead to a personalized treatment plan and faster response and remission for patients than with standard care [15].

2. Expert opinion

A better understanding of the neurobiology of depression has provided a rationale for individualized drug selection both initially and after unsuccessful treatment. The novel multimodal/multifunctional ADs that engage multiple targets by different modes of action may provide an attractive option. Monotherapy with multimodal/multifunctional ADs has many advantages in current clinical practice and especially in outpatient settings, mainly simplicity of regime (associated with a better adherence to treatment) and safety. This strategy should be tested in the subpopulation of patients experiencing pharmacoresistant depression.

During the era of psychopharmacology, there has been a progression from general therapies that were identical for all patients to individualized treatment. It is time to fulfill the promise of personalized medicine in psychiatry. Pharmacogenomic testing may help to guide treatment decisions in the near future. The clinical use of pharmacogenomic testing for individual genes has largely failed to show clinical utility. Pharmacogenomics currently utilize genetic information to predict responses to medications on a personalized level based on known gene–drug interactions for both pharmacokinetic and pharmacodynamic genes. The evidence for the clinical utility of ‘combinatorial pharmacogenomics’ is mounting.

The curricula for psychiatrists should be continuously innovated and new advances in the field should be included. Medical students and young psychiatrists are obtaining new knowledge, mainly through the internet, and this should be taken into consideration.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was supported by the Ministry of Education, Youth and Sports of the Czech Republic CEITEC 2020 (LQ1601).