Precision Psychiatry Approach to Treat Depression and Anxiety Targeting the Stress Hormone System – V1b-antagonists as a Case in Point

• Abstract
• Introduction
• The Stress Hormone System in Health, Depression, and Anxiety Disorder
• Drugs Targeting Impaired Glucocorticoid Receptor Function
• A Case in Point: Blocking the Depressiogenic and Anxiogenic Effects of Vasopressin with a V1b Antagonist
• Prediction of Clinical Response to V1b-Receptor Antagonists Using Companion Tests
• Conclusion
• References

Abstract

The future of depression pharmacotherapy lies in a precision medicine approach that recognizes that depression is a disease where different causalities drive symptoms. That approach calls for a departure from current diagnostic categories, which are broad enough to allow adherence to the “one-size-fits-all” paradigm, which is complementary to the routine use of “broad-spectrum” mono-amine antidepressants. Similar to oncology, narrowing the overinclusive diagnostic window by implementing laboratory tests, which guide specifically targeted treatments, will be a major step forward in overcoming the present drug discovery crisis.

A substantial subgroup of patients presents with signs and symptoms of hypothalamic-pituitary-adrenocortical (HPA) overactivity. Therefore, this stress hormone system was considered to offer worthwhile targets. Some promising results emerged, but in sum, the results achieved by targeting corticosteroid receptors were mixed.

More specific are non-peptidergic drugs that block stress-responsive neuropeptides, corticotropin-releasing hormone (CRH), and arginine vasopressin (AVP) in the brain by antagonizing their cognate CRHR1-and V1b-receptors. If a patientʼs depressive symptomatology is driven by overactive V1b-signaling then a V1b-receptor antagonist should be first-line treatment. To identify the patient having this V1b-receptor overactivity, a neuroendocrine test, the so-called dex/CRH-test, was developed, which indicates central AVP release but is too complicated to be routinely used. Therefore, this test was transformed into a gene-based “near-patient” test that allows immediate identification if a depressed patient’s symptomatology is driven by overactive V1b-receptor signaling. We believe that this precision medicine approach will be the next major innovation in the pharmacotherapy of depression.

Introduction

Precision medicine has made overwhelming progress in oncology, where biomarker-led therapies have become standard for many molecular-defined targets [1]. Other medical disciplines, for example, cardiology [2] and dermatology [3] are also catching up with this paradigmatic shift. Psychiatry faces particular challenges in adopting the promise of personalized or precision pharmacotherapy, as drug targets are less obvious [4].

Around 70 years ago, the first antidepressants were discovered serendipitously by astute clinician-scientists in Switzerland, Kuhn [5] and Angst [6]. Since then, tremendous effort and progress in molecular and systemic neuroscience has accumulated a vast amount of knowledge on cells, genomics, and circuits involved in the mechanisms of monoamine-based antidepressants. However, it is still unclear whether the mechanisms that we know and understand are those that make the drugs work we prescribe. In light of this sobering fact, it is not surprising that ketamine and psychedelics, whose relevant mechanisms of action are even more obscure, gain increasing attention. It is fair to say that ketamine and psychedelics, like psilocybin and others, present another level of serendipity: their potential as antidepressants was discovered decades after their introduction as anesthetic (ketamine) or hallucinogenic psychedelic drugs [7] [8].

Thus, up to now, psychiatry has taken a completely different turn than oncology and most other medical disciplines. A major constraint to change this is the attitude of regulatory agencies that keep hold of the current way too broad diagnoses, despite scientific evidence suggesting that patients categorized under a certain diagnosis do not share the same neuropathology. A recent sibling study using comprehensive registry data documented differential genetic heritability as well as distinct genetic components across diverse subgroups of depression, underscoring the heterogeneous etiopathology of the disorder [9]. Specifically, patients who meet all criteria for major depressive disorder (MDD) and also perfectly match on various scales characterizing depressive psychopathology, do not necessarily have the same causal mechanisms and do not clinically respond to the same antidepressants. Even the same patient with MDD does not necessarily benefit from the same drug in repeated disease episodes. Heterogeneous neuropathology is a pertinent issue to be carefully considered. Understandably, this fact is unwanted in the pharma industry, which has embraced the “one-size-fits-all” concept, in analogy to broad-spectrum antibiotics. Across generations of newly developed antidepressants, drugs that were safe and had a better side effect profile emerged, but were not more efficacious [10]. The current antidepressants are working, but they do so in too few patients, take too long to show results, achieve too low remission rates (around 25% in the first treatment course), but still have too many side effects [11]. Last but not least, practicing clinicians became comfortably adjusted to paying more attention to tolerability and side effects than clinical efficacy, as that shows little difference across the current antidepressants.

Another impediment is that any major innovation on the route to precision medicine in psychiatry warrants major efforts to overcome the current well-established clinical routine and the shyness of practicing clinicians toward novel approaches. Heading for new shores in drug discovery was, in the beginning, burdensome. First pharmacogenetic approaches interrogating a link between a patient’s genotype and response to drugs that target the serotonin space had mixed results [12] [13]. Also, attempts to develop a genetic tool with genotypes of many different genes, deemed to be important components of antidepressant signaling pathways, were unsuccessful and failed to make it to the market [14] [15]. The main reasons for these failures were limited predictive power and missing replication. Consequently, regulators did not approve and payers did not reimburse.

A telling example of how scientific findings get lost in translation to the patient is the poor acceptance of a gene test that predicts whether or not a given antidepressant is able to pass the blood-brain barrier at quantities needed to enter regions where pathology is located [16]. This test (named ABCB1-test), in combination with the measurement of plasma drug levels, was expected to be of major interest to practicing clinicians. Studies testing the clinical benefit of this test among inpatients proved that treatment outcome is better if drug choice is guided by the ABCB1-test result [17] [18]. Despite being on the market in several countries and reimbursed by payers in Switzerland, the acceptance was poor.

That an antidepressant drug must be present in adequate concentrations at the locus of neuropathology is well understood. One of the things not widely understood is that a drug, which is bioavailable in the brain area considered to be causally relevant, does not necessarily work if the mechanism of drug action does not match the disease-causing mechanism. Silberbauer et al. [19] used positron emission tomography combined with magnetic resonance imaging (PET)/(MRI) and were able to show that binding of a serotonin reuptake inhibitor (SSRI) to its molecular target, the serotonin transporter (SERT), depends on the ABCB1 genotype encoding P-glycoprotein that transports the drug from blood vessels into brain tissue. Knowledge of the ABCB1 genotype and binding of the drug to the SERT, however, is irrelevant if the patient does not have a serotonin-related causality.

In conclusion, it becomes clear that without intensive educational efforts, major strides in personalized antidepressant drug development will not happen, to the detriment of patients. This lesson has to be learned when efforts are being made to realize the promise of personalized precision medicine in depression therapy [4].

On the route to the discovery and development of personalized depression therapy directed by laboratory tests, this article focuses on the HPA-axis and takes advantage of the wealth of scientific knowledge on how this hormonal system is regulated and the biological reasons for its hyperactivity in 30–50% of patients with depression. The pertinent question is: Would these patients respond better to a drug directly targeting the HPA system? The goal of the present treatise is to briefly summarize a variety of previous quite different attempts to administer drugs that interfere with the regulation of the HPA system [20].

We take the neuropeptide vasopressin as a case in point: Vasopressin is one of the master hormones in the brain governing HPA activity as well as depression- and anxiety-like behavior in animal models. It is outlined how a biomarker and/or a gene test can be used as a companion test, enabling identification of those patients that are likely to respond to a V1b-receptor antagonist, a drug that blocks the action of vasopressin in the brain and the anterior pituitary.

The Stress Hormone System in Health, Depression, and Anxiety Disorder

If a situation is perceived as a psychological or physical endangerment, the organismic homeostasis is perturbed, and to adapt to the stressor, a number of behavioral and physiological responses are set in motion to attempt reinstatement of homeostasis [21]. The stress response is characterized by rapid activation of the sympathetic nerve system, which triggers the release of catecholamines, mainly from the adrenal medulla and to a limited extent of corticosteroids from the adrenal cortex. This fast response is followed by increased secretion of so-called stress hormones, including corticotropin (ACTH) from the anterior pituitary, which stimulates corticosteroids at the adrenal cortex. The master hormones in the brain that activate the stress hormones are two neuropeptides: corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) (see [Fig. 1]). CRH and AVP are synthesized in the paraventricular and supraopticus nuclei of the hypothalamus, whereas CRH is transported via blood vessels to the anterior pituitary, AVP comes via axonal transport to the posterior lobe of the pituitary. Both neuropeptides coordinate the behavioral response to stress and also, via ACTH secretion, of corticosteroids, mainly cortisol in humans [22].

Cortisol exerts pleiotropic actions through two corticosteroid receptors, the mineralocorticoid- and glucocorticoid receptors (MR and GR) and when activated by cortisol, they regulate many steroid-hormone responsive genes [23]. Both, the MR and the GR, bind to cortisol, but the MR has a tenfold higher affinity. The ability of GR and MR to form homodimers (GR-GR and MR-MR) and heterodimers (GR-MR) has the advantage of allowing responsivity to a wide concentration range of cortisol, as it happens particularly when coping with stress [24].

An important role of ligand-activated GR and MR is the reinstatement of stress hormone homeostasis. The binding process is accompanied by dissociation of chaperone molecules which impact the three-dimensional structure of both receptors and determine the affinity at which corticosteroids bind. One particularly important chaperone molecule is the FK506 binding protein 51, abbreviated FKBP51, which is coded by the FKBP5 gene. Besides its name-giving role in modulating the immunosuppressive effects of FK506, FKBP51 also acts as a co-chaperone to the heat-shock protein HSP90 to modulate activation and sensitivity of most steroid receptors, including the GR. While HSP90 is essential for GR maturation, activation, and translocation [25], FKBP51 negatively affects its sensitivity for binding glucocorticoids [26] [27], thus acting as a functional inhibitor for the GR [28].

After activation through steroid binding, the receptors become transcription factors and bind to genes that are regulated by positive or negative response elements, which means that the steroids can enhance or suppress respective gene activity. The genes encoding preproteins for CRH and AVP in most parts of the limbic system and for ACTH at the pituitary are regulated by negative response elements, and that is why elevations of cortisol suppress the expression of these drivers of the HPA system. If the stress exposure is terminated, plasma ACTH and cortisol concentrations return to baseline through that negative feedback mechanism ([Fig. 1]).

The overall effect of this regulatory mechanism in humans can be checked by a simple experiment, i. e., the dexamethasone suppression test (DST). In this test, a low dose (1–1.5 mg) of the synthetic steroid dexamethasone is orally administered around midnight, and at 4 p.m. the next day, plasma cortisol concentrations are measured. In healthy controls, the plasma cortisol levels are beyond a certain threshold (4–5 microgram/deciliter) because dexamethasone, through negative feedback, represses the gene encoding the preprotein for the ACTH synthesis at the level of the pituitary, resulting in low cortisol output from the adrenal cortex. In about 30 to 50% of patients with depression, the cortisol levels are not adequately suppressed, and both, plasma ACTH and cortisol concentrations, are above the threshold.

In the early 1980s, some clinician scientists propagated that this test would allow to confirm the diagnosis of melancholia, a subtype of severe depression [29]. Neither this diagnostic subtype nor the diagnostic specificity of the DST for this subtype have stood the test of time. Instead, a pertinent question was raised: What is the relationship between depressive symptoms in the course of time and the outcome of serial DST administrations? Several clinically meaningful observations were made: (1) DST non-suppression stepwise normalizes prior to resolution of depressive symptoms, (2) failure to normalize is prognostically ominous, and (3) if the DST is normalized in remitted patients but returns to non-suppression, this may indicate an impending relapse [30].

These time course patterns of psychopathology linked to stress hormone regulation strongly suggest that normalization of the initially defunct HPA axis is an essential requirement for the clinical resolution of depression. Likewise, if the HPA axis gets perturbed, the onset of a depressive episode is likely. These findings clearly oppose the long-held interpretation that HPA overactivity among depressives is merely signaling that these patients experience depression as very stressful. In contrast, it seems that in a subgroup of patients, the development of an HPA hyperdrive precipitates depressive symptomatology, which is a cornerstone of the corticosteroid receptor hypothesis [31].

Because the drivers of the HPA axis, CRH and AVP in the CNS, and ACTH at the pituitary are under negative feedback control and suppressed by steroid-activated GR and MR, a plausible explanation of the above findings is decreased sensitivity and/or a decreased number of these receptors. Another neuroendocrine test in support of this view is the combined dexamethasone/CRH-test (dex/CRH-test). This test administers a low dose of dexamethasone around midnight, and at 3 p.m. the next day, a dose of 1oo micrograms human-CRH is intravenously injected. The amount of ACTH and cortisol released after CRH administration is much higher among depressives when compared with controls [32] [33] [34]. Heuser and coworkers [35] showed that many more patients had abnormal dex/CRH-test results than DST non-suppression, indicating that this test detects HPA dysregulation with higher sensitivity. This higher sensitivity is also important clinically because a number of explorative studies showed that the dex/CRH-test predicts an increased risk for relapse [36] [37] [38]. Additionally, Ising et al. [39] showed in a large study recruiting 50 patients that dex/CRH-test results are clinically important as they predict clinical outcome and prognosis. It was also suggested that the dex/CRH-test could serve as a surrogate marker useful in drug discovery and development [4].

The elevated stress hormone output after CRH administration among dexamethasone pretreated depressives was surprising. The underlying mechanistic explanation is that after dexamethasone administration, less ACTH and cortisol are secreted and the corticosteroid receptors in the brain become unoccupied because low dosages of dexamethasone do not penetrate into the brain to compensate for the withdrawal of natural corticosteroids. This loss is sensed as an alarm signal prompting activation of the HPA axis by stimulating neuropeptides CRH and AVP. If, under such circumstances, CRH is significantly elevated by intravenous administration, it synergizes with increased brain-derived AVP, which results in overriding the dexamethasone suppression and consequently increases ACTH and cortisol. It is important to note that it needs dexamethasone administration prior to CRH to reveal AVP overactivity. Without dexamethasone, intravenous CRH-elicited ACTH release is blunted because of the cortisol-induced negative feedback, which is avoided when cortisol biosynthesis is impaired by metyrapone pretreatment [40]. Without dexamethasone pretreatment, AVP secretion is too low and does not play a role [41] [42].

The hypothesis that AVP is the driver of the dex/CRH-test, was confirmed by a study of von Bardeleben et al. [43]. In that study, normal controls, pretreated with low-dose dexamethasone, neither CRH nor AVP infusions, when given alone, were able to increase HPA hormone secretion. However, if both neuropeptides were given simultaneously, cortisol and ACTH levels in controls were high and similar to those of depressives receiving the dex/CRH-test, as said before. If depressives get dexamethasone before iv. CRH administration and achieving the same stress hormone levels as controls receiving dexamethasone and both neuropeptides, CRH and AVP, it is reasonable to conclude that enhanced HPA activity in the dex/CRH test of patients with depression is a surrogate for central AVP overactivity. Among patients with depression increased AVP is synthesized and released from parvocellular hypothalamic neurons (PVN), from where it is transported to the anterior pituitary to synergize with CRH and elevate plasma ACTH and cortisol levels in these patients. This enhancement of central AVP is plausibly explained by the limited sensitivity of GR, which fails to adequately restrain AVP gene expression. The elevation of AVP expression is also shown in post-mortem brains of patients with depression [44].

Still, another strong argument that GR sensitivity is a key mechanism explaining these neuroendocrine findings is a study by Modell et al. [45]. This study administered different dosages of dexamethasone prior to the CRH challenge in patients with depression and healthy controls and found that HPA hormone suppression in the dex/CRH test requires higher dexamethasone dosages among depressed patients, which corroborates the view that GR function is impaired in these patients. That study was in line with studies employing a transgenic mouse model expressing GR antisense mainly in neuronal systems and served as a model of those forms of depression where impaired GR function prevails over other potential pathologies. In these mutants, higher dexamethasone dosages are needed to achieve corticosterone suppression when compared to controls [46]. The importance that GR and MR are not only mediators of acute hormonal, metabolic, and behavioral adaptation to stress exposure but also act as mediators of long-term effects of early adversity, which may convey risk for anxiety disorder and depression, is key to current research related to gene-environment interaction [47].

Drugs Targeting Impaired Glucocorticoid Receptor Function

Too few patients with depression benefit from antidepressants, which, as said before, take too long until they work, have poor remission rates, and have too many side effects. But if they work, they do so regardless of the HPA status at the beginning of therapy. The reason why they work independently from initial HPA status is because of their manifold unspecific pharmacological actions.

Whether antidepressants act directly at MR and/or GR was studied by Reul et al. [48] [49], who treated rats for 5 weeks with antidepressants that exhibited different pharmacological primary effects. These authors found that the treatment had decreased their plasma ACTH and corticosteroid concentrations. When analyzing the MR and GR binding capacity, it turned out that the first change was in MR binding, which increased in about 1 week, followed by increased GR capacity [48] [49]. The initial increase in MR capacity followed by increased GR capacity is of particular interest because the observed upregulation of MR and GR seems to be the initial step necessary to decrease the expression of central CRH and AVP. Complementary experiments using transgenic mice that express GR antisense and were treated with antidepressants not only showed normalized HPA activity [50], but also the resolution of behavioral signs and symptoms reminiscent of human depression [51]. While these explanations are conclusive, the pleiotropic effects of corticosteroids allow, as suggested by in vitro cell studies, that many other effects may come into play [52].

The abundant experimental evidence of the central role of functional impairment of GR and MR, as well as the detrimental effects of excessive cortisol, stimulated a number of clinical studies that tested the effects of direct interventions at the level of corticosteroids and their related receptors [53]. The first example of targeting corticosteroid receptors does not remediate GR and MR function but rather works by reducing damage caused by excessive cortisol secretion. Patients suffering from a depressive subtype termed psychotic depression, characterized by severe impairments at all levels, such as sleep, exhaustion, cognition, feeling worthless and guilty, and having unrealistic thoughts of various endangerments including health, livelihood, and loss of reputation, typically have excessive HPA-axis activity. It is suggested by Schatzberg and colleagues [54] that high plasma cortisol levels may enhance dopamine activity in brain areas believed to be relevant for the emergence of psychotic symptoms. Clinical routine uses dopamine receptor antagonists as treatment in such cases. Treatment with RU 486 (Mifepristone), an antagonist at GR and progesterone receptors, was found to have therapeutic effects by preventing GR-mediated upsurge of dopamine, which may cause psychotic symptoms [55]. Another possible mechanism is that the blockade of GR by RU486 disrupts negative feedback and, in turn, upregulates MR, which, as outlined above, suppresses CRH and AVP. In this context, the study by Otte et al. [56] is of note as these authors used an MR-agonist, fludrocortisone, as augmentation of an SSRI standard treatment and observed that these patients had an accelerated onset of treatment response and decreased plasma cortisol levels when compared to placebo. In that study, the effect of the MR antagonist spironolactone was also tested, but contrary to expectations caused by a pilot study using amitriptyline (Hundt et al., unpublished observation, see [57]), the MR antagonist did not worsen clinical outcome despite the increase in plasma cortisol levels. Probably, the different effects on the MR capacity of the SSRI in one study and of amitriptyline in the other have obscured the effects of spironolactone.

Another attempt to challenge corticosteroid metabolism directly is a study that investigates metyrapone in a randomized placebo-controlled trial as an augmentation of standard treatment in depression [58]. Metyrapone is an inhibitor of steroid-11ß-hydroxylase needed for steroid biosynthesis. Thus, metyrapone deprives the organism to a certain extent of natural corticosteroids. The authors observed favorable response in patients receiving metyrapone in addition to standard serotonergic antidepressants, which was most likely associated with upregulated MR and GR capacity preventing excessive production of CRH and AVP. The effect of metyrapone and its active metabolite is the inactivation of an enzyme that is necessary for the final step in the synthesis of cortisol. This results in an abundance of steroids that can be modified into neuroactive steroids, which by themselves have psychotropic actions [59] [60], therefore, it is difficult to judge which mechanism accounts for the reported positive clinical effect of metyrapone.

Interventions at peripheral hormones interfere primarily with the upstream effects of all those corticosteroids and their metabolites that penetrate into the brain; another option is targeting those neuropeptides directly in the brain, which regulate peripheral stress hormones via downstream effects. Following the seminal finding and characterization of corticotropin-releasing hormone (CRH) by Vale et al. [61], a vast amount of evidence accumulated that CRH is most likely not only driving the HPA axis, but also causes a number of signs and symptoms in experimental animals that resemble human anxiety and depression. These findings suggested an important role of CRH in the development and course of depression and anxiety disorders (reviews: [57] [62]). The evidence from behavioral studies was strongly supported by neuroanatomical studies showing that neuronal projections send CRH from its origin in the hypothalamus to CRH1-receptors (CRHR1) in brain areas relevant for depression and anxiety [63]. CRH was also found elevated in the cerebrospinal fluid of depressives [64]. Also, CRH binding sites were reduced as a consequence of increased ligand exposure in the frontal cortex of depressed suicide victims [65], and depressives had increased CRH-expressing neurons in the PVN of their hypothalamus [66]. That antidepressant effects are directly linked to potentially depressiogenic CRH was suggested by Heuser et al. [67], who showed a decrease in CRH in cerebrospinal fluid of depressed patients under antidepressant treatment. A pulsatile administration of CRH during sleep produced sleep-EEG changes in healthy controls that were similar to changes seen among many patients with depression. The main changes were a reduction of slow wave sleep and rapid eye movement sleep, while shallow sleep increased in both male and female healthy volunteers [68] [69]. This effect cannot be attributed to CRH-prompted elevation of cortisol because when administered prior to sleep, cortisol does the opposite, and when secreted during sleep, it suppresses central CRH. Similar effects were reported by Vgontzas et al. [70] who also reported these sleep-EEG findings, which were more pronounced in middle-aged than in young healthy men. When patients with depression were treated with a CRHR1-antagonist, the depression-related sleep-EEG findings disappeared [71]. In accordance with these clinical study results is a complementary preclinical experiment employing genetically modified transgenic mice, in which CRH was conditionally overexpressed under stress [72]. These mice showed depression-like sleep-EEG changes, i. e. increased REM- activity, as many depressed patients do. These changes disappeared following CRHR1-antagonist treatment [73].

All these findings led to massive investments in almost all big pharma industries aiming to develop drugs that block CRH at its cognate CRH1-receptor. A first exploratory study, where inpatients with severe major depression were treated with R121919, the first clinically available CRHR1 antagonist, showed positive clinical results that exerted better results at higher dosages. After cessation of treatment, patients got worse [74]. This encouraging clinical study, as well as a continuation of convincing basic research, culminated in a series of large randomized controlled trials in major depression, anxiety disorders, and posttraumatic stress disorder (PTSD), which all were negative. Spierling and Zorrilla [75] analyzed the negative studies and surmised that some form of prescreening, for example, checking HPA function, may have helped to gain better results. It seems that drug developers were still trapped in the higher realm of antidepressant blockbusters, yielding enormous profits. The main failure in all these CRHR1 studies was that a drug specifically targeting its receptor works only if the respective patient has hyperactive CRH neurons in the brain that make him or her ill. The activity of these central nervous system neurons cannot be judged by measuring corticotropin or cortisol in blood or elsewhere. CRH might be elevated via neural projections in relevant brain areas, remote from the hypothalamus, resulting in depression and anxiety symptoms. The activity of CRH secretion, transported from the hypothalamus via blood vessels to the anterior pituitary, is linked to a circadian rhythm, which also underlies plasma ACTH and cortisol secretion. These secretory patterns are in the normal range unless exposure to a stressor demands adaptation, which results in enhanced HPA-axis activity. There are also differences in CRH secretory activity, which project to brain areas involved in depressive pathology. In other words, if someone is suffering from depression, this may be caused by CRH overactivity in cortical areas, which is not necessarily reflected by enhanced CRH activity in the hypothalamic-pituitary space. In other clinical conditions, CRH might be overactive in both directions. Therefore, it was predicted that it needs a combination of physiologic and genetic biomarkers as well as clinical examination to identify patients whose clinical condition is caused by overactive CRH neurons in relevant brain areas and, therefore, are likely to respond favorably to CRHR1-antagonists [76].

The situation is somewhat different and even more complex for vasopressin (AVP in humans, VP in rodents), which is a neuropeptide, that when synthesized from magnocellular nuclei in supraoptical cell clusters of the hypothalamus, is transported via axons to the posterior lobe of the pituitary to serve blood pressure regulation, while both, hormonal activity via pituitary and behavioral effects via neuronal transport, are governed by hypothalamic PVN nuclei. It is important to understand the following strategy in the development of a companion test allowing to predict which patient with depression will benefit from treatment with vasopressin type1(V1b-) receptor antagonists [77].

A Case in Point: Blocking the Depressiogenic and Anxiogenic Effects of Vasopressin with a V1b Antagonist

AVP is a cyclic nonapeptide that serves two main functions: (1) regulation of blood pressure and water conservation mainly produced by magnocellular nuclei in supraopticus cell clusters (SON), transported via axonal transport to the posterior pituitary and released into the peripheral circulation and (2) regulation of the HPA-system via AVP secreted from the parvocellular system of the hypothalamic PVN cells projecting axons to the median eminence from where dendrites secrete AVP into the pituitary portal vessels and subsequent binding at V1b-receptors located at the anterior pituitary resulting in ACTH synthesis and release. Several other hypothalamic and extrahypothalamic nerve cells contain AVP; these include CRH neurons and terminals of CRH axons, highlighting that the neuroanatomy of AVP and CRH systems are intrinsically intertwined [77] [78]. This extends to stress adaptation and the development of stress-related diseases on the behavioral level [23]. Of particular interest are AVP-containing neurons in the medial amygdala, a nerve cell complex that is, together with other nuclei, involved in fear, anxiety, and memory. From there, projections reach limbic structures such as the ventral hippocampus, whose main functions involve the regulation of emotions in response to stress exposure. While AVP from magnocellular systems depends upon osmotic demands, parvocellular secretion independent from osmotic status is activated by stressors, not all AVP systems are functionally separated in a strict way and are, among others, active in the suprachiasmaticus nucleus, bed nucleus of the stria terminalis, and the lateral septum.

Enrichment of AVP in various brain areas, including those that are believed to be involved in depression and anxiety, can be induced by various stimulants related to stress, including physical and emotional challenges. For example, as shown by Wotjak et al. [79], the forced swim test, often used as a screening test for antidepressant drug candidates, is a stressor on both levels, emotional and physical. This test causes dendritic release of rodent vasopressin (VP) within both, the SON and the paraventricular nuclei, as well lateral septum and amygdala. In contrast, a purely emotional stressor, such as the social defeat paradigm, induces only the dendritic release of VP from the PVN but has no effect on SON or VP released from the posterior pituitary into peripheral circulation. Taken together, the neuroanatomical and physiological knowledge about VP has supported the view that this peptide is not only involved in the regulation of blood pressure but also plays an important role in mediating anxiety-like behavior. We owe the seminal work of David de Wied [80] the insight that the brain is an important target for peptide hormones and especially how central activity of VP induces many behavioral, emotional, and cognitive effects. Shortly afterwards, the assumption that increased central release is possibly involved in the causality of depression was discussed by Gold and colleagues [81]. A host of behavioral studies combined with various sophisticated technologies that allow interrogation of region-specific effects of VP on anxiety- and depression-like behavior indicates that the VP system is an interesting target for drug discovery in fighting human anxiety and depression [78].

Among the many behavioral studies exploring the effects of VP in the context of modeling development and the course of depression and anxiety disorders in experimental animals, studies by Landgraf [77] are particularly instructive: Wistar rats were selectively bred for high- and low-anxiety-like behavior, and it was shown that rats with high anxiety-like behavior (HAB-rats) had enrichment of VP expression when compared with animals with low anxiety-like behavior (LAB-rats). The anxious animals with increased VP-activity also had increased HPA activity, and as patients with depression, they also showed escape of plasma cortisol concentration after dexamethasone administration [82]. In this context, it is of note that hypothalamic VP-producing neurons not only serve to regulate adrenocortical activity via ACTH secretion but also project to selective brain regions where VP binds to V1b-receptors, stimulating anxiety- and depression-like behavior [83]. The pertinent questions that arise are: is VP conveying these symptoms directly via cognate V1b receptors, and would anxiety-like behavior disappear if these receptors are blocked? Further, would loss of overstimulation of VP receptors be a therapeutic option [78]?

The first set of experiments using a nonspecific V1-receptor suggested this possibility as it could be shown that the application of the drug into the PVN by inverse microdialysis reduced anxiety-like behavior in male HAB rats. In the aforementioned forced swim test, several behavioral aspects deemed to be depression-like, were also reduced by the V1-antagonist [84]. In the same line was a study that showed a decrease in anxiety-like behavior along with reduced VP expression in the PVN of HAB rats after they were treated with an antidepressant [85]. Also, from a genetic angle, an important role of VP signaling via V1b receptors was shown. Using CD1-mice that were in analogy to Wistar rats selectively bred for high- and low-anxiety-like behavior (HAB- and LAB-mice) and, similar to rats, had increased expression of the VP gene in the hypothalamic PVN and SON nuclei, Bunck et al. [86] found a hypomorphic LAB-specific VP allele associated with a 75% reduced transcription rate when compared with the HAB-specific allele. The different expression levels of the VP gene correlated with anxiety- and depression-like behavior in the respective behavioral assays. In the same direction, a study on humans identified a major SNP haplotype of the V1b receptor associated with decreased risk for depression [87]. The authors concluded that the observed associated haplotype is possibly protective and suggested that patients and controls carrying this haplotype should undergo a dex/CRH test to examine whether this genetic variation modifies HPA regulation, possibly via enhancement of VP. The view that the dex/CRH-test is an indirect surrogate marker for elevated paraventricular VP is strongly supported by a study that administered the dex/CRH-test to male HAB- and LAB-Wistar rats [88] and observed that animals from the HAB line showed significantly higher ACTH- and corticosterone release than their LAB counterparts. This neuroendocrine finding was associated with increased synthesis and secretion of VP in male HAB rats, as evidenced by in situ hybridization and microdialysis. When male animals with high anxiety undergoing the dex/CRH-test were pretreated with an unspecific V1a,b-antagonist, the plasma ACTH and corticosterone concentrations were much lower than without the antagonist. Notably, such effects were much less pronounced in female animals, and whether such gender differences also extend to human needs be shown.

These and many other basic science experiments [77] have prompted the pharmaceutical industry to invest in research and development of potent antagonists at the V1b-receptor, which is not only richly expressed in the anterior pituitary but also in many brain areas likely to be involved in the neuropathology of depression [89]. These sites include the hypothalamus, lateral septum, hippocampus, olfactory bulbs, prefrontal cortex, and amygdala. To date, eight nonpeptidergic chemical molecules that selectively block V1b-receptors after oral administration were thoroughly studied in preclinical experiments and provided encouraging results (see reviews: [90] [91]). Three of these compounds made it into clinical development. The first compound was SSR149415, from the French company Sanofi, which was able to suppress stress hormone release, norepinephrine release, and behavioral changes, as they occur following stress exposure [92]. In a series of experimental assays using animal models, the effects of SSR149415 on anxiety- and depression-like behavior were studied by Griebel et al. [93], who showed that this compound exerts behavioral changes consistent with antidepressant properties. Other related V1b-antagonist drug candidates also showed effects similar to conventional antidepressants, but it is of note that not all reported antidepressant-like effects were consistent [94]. That is particularly true for the forced swim test, which points to the possibility that this test indicates only potential antidepressant-like effects among monoamine-based compounds.

Two randomized, double-blind, placebo-controlled trials in major depression, examined two different dosages (100 mg and 250 mg) of SSR149415 versus paroxetine in one study and escitalopram in the other. One controlled study tested SSR149415 versus paroxetine in generalized anxiety disorder [95]. In all three studies, it turned out that SSR 149415 was safe and well tolerated according to ECG results and endocrinology, such as ACTH response to a CRH challenge test. In one of the depression studies, the higher dosage produced significantly greater reductions in the Hamilton Depression Scale score when compared with placebo. A similar trend was seen in secondary endpoints, such as the Montgomery Asberg Depression Scale. Because the comparator antidepressant escitalopram exerted only nonsignificant reductions on the Hamilton Depression Scale, the informative value of that study was limited and led the management of Sanofi to stop further development.

Another drug candidate is ABT-436, from the US company Abbott, which was tested in a controlled trial against placebo-defined changes in basal HPA parameters as the primary endpoint. Basal as well as dynamic HPA parameters, such as stress hormone response to CRH, were lower in patients treated with the V1b-antagonist as compared with placebo [96] [97]. In a subsequent analysis, it was observed that patients responded favorably according to subscales of the Mood and Anxiety Symptom Questionnaire (MASQ), but favorable effects on the Hamilton Depression Scale score were absent, which can be attributed to the short duration (7 days) of the trial [97]. In that context, it is interesting that symptom severity on the MASQ correlated with plasma cortisol concentration, which is unsurprising and had been previously reported using plasma and urine levels of cortisol, as well as related findings using the dexamethasone suppression test.

Kamiya et al. [98] explored the efficacy and safety of TS-121 from the Japanese company Taisho in a randomized double-blind, placebo-controlled trial as adjunctive to antidepressant treatment in patients with major depression. In that trial, TS-121 exerted reductions in several established depression and anxiety scale scores, which, however, were nonsignificant. Interestingly, patients who had initially increased baseline urinary cortisol concentrations, as well as increased cortisol in their hair, responded better when treated with TS-121 than with a placebo. Of particular interest is that the authors determined the dose, expected to be optimal, using positron emission tomography (PET) with a PET tracer [99]. They found that a 50% occupation of V1b-receptors with TS-121 is needed at the anterior pituitary level to achieve behavioral antidepressant-like effects in animal models. Similar to ABT-436, the dosage chosen by Kamiya et al. using TS-121 also resulted in a reduction of plasma cortisol concentration [98]. Because depressive psychopathology is generated in the brain rather than the pituitary, it would be interesting to investigate to which extent oral ingestion of the clinically explored V1b-antagonists (SSR 149415, ABT-436, and TS-121) occupy central V1b-receptors, particularly those deemed to be relevant for depression and anxiety symptoms.

Prediction of Clinical Response to V1b-Receptor Antagonists Using Companion Tests

In essence, targeting the neuropeptide stress-hormone network is strongly supported by basic neuroscience, and almost all pharma industries invested in research and development of orally available brain penetrant nonpeptidergic compounds that specifically block CRH1- or V1b-receptors. Despite promising preclinical results, none of the compounds made it to the market because the majority of controlled clinical trials were negative, putting this innovative approach on hold [76]. Neuropeptide drugs, such as CRHR1- or V1b-antagonists, are selective and specific as they only target the respective receptors and do nothing else than prevent the action of CRH or AVP at these receptors. The consequence is that their clinical efficacy depends on the presence of increased activation of these receptors. That means, if the mechanism causing depression in a given patient is not enhanced AVP-V1b signaling, blockade of the V1b-receptor will not have any beneficial clinical effects. In analogy, a patient having depression that is not caused by CRH-CRHR1 hyperactivity will not benefit from a CRHR1-antagonist. Under this aspect, published controlled studies with CRH1- and V1b- antagonists that did not prescreen their patient population accordingly are not negative but failed.

The pertinent question is: How can we identify a patient where the underlying pathophysiology is dominated by increased central AVP-V1b-signalling? AVP participates in the stress-elicited secretion of ACTH and cortisol and potentiates the ACTH-stimulatory effects on pituitary corticotrophs [100]. AVP is, together with CRH, increased in paraventricular neurons, and its V1b-receptor heterodimerizes with CRHR1-receptors [44]. Without ambient CRH, AVP has little effect on HPA activity, but after a challenge, if hypothalamic AVP synthesis is no longer suppressed by cortisol, it is elevated in a subgroup of depressive patients, as evidenced by the dex/CRH-test (see above).

The most direct approach is measuring cortisol in plasma, urine or hair, which Katz et al. have shown to be a reasonable approach [97] using ABT-436 and by Kamiya et al. [98] using TS-121. Although not statistically significant, the authors found that the content of plasma cortisol concentration separated the patients according to clinical response. One caveat of this approach is that CRH is a complementary stimulant for AVP. This neuropeptide, unlike CRH, does not act alone, and both neuropeptides are intrinsically intertwined: depending on the duration of stress, the AVP:CRH ratio changes over time, and prolonged HPA overactivity shifts the ratio to higher readouts, indicating under chronic stress, an increased parvocellular AVP release into the portal vessels from which the neuropeptide enters the anterior pituitary and binds to V1b-receptors [101].

Another source of HPA activity, independent from direct neuropeptide effects on ACTH synthesis, is the sympathetic nervous system. Before being exposed to an acute stressor, rats were chronically stressed by a mix of restraint, foot shock, and cage tilts [102], which resulted in elevated levels of corticosterone. Administration of a CRHR1 antagonist reduced ACTH, but not corticosterone in chronically stressed animals [103]. This study indicated that an increased sympathetic activity contributes to plasma corticosterone concentration in the context of chronic stress independently from HPA activity. If these experimental findings in animals can be extended to the situation in humans, the activity of the sympathetic nervous system may be another source of uncertainty when attributing peripheral cortisol secretion and its plasma, urine, or hair concentration to centrally released AVP.

As outlined above, the dex/CRH-test, which sensitively depicts aberrant regulation of the HPA axis in depressive patients [35], is reflecting enhanced anterior pituitary release of AVP from paraventricular and supraoptical nuclei. Therefore, it was suggested to use this test as a prescreen that allows prediction if a patient’s depression is largely due to central overactivity of AVP-V1b-signalling [76] [90]. Inasmuch as the outcome of the dex/CRH-test may be taken as a proxy for PVN-released AVP, it is also obvious that the conductance of this neuroendocrine test is too complicated to be broadly accepted. Therefore, an attempt was made to search for genetic differences between patients who were suffering from a depressive episode and had either normal or high plasma ACTH and cortisol secretion when the dex/CRH-test was administered. To do so, a genome-wide interaction analysis was conducted with a single nucleotide polymorphism (SNP) with upstream transcriptional effects on the V1b-receptor gene as an anchor variant. Using a large patient sample of over 350 patients with major depression, SNP-by-SNP interactions were evaluated regarding their potential to predict high versus low release of ACTH. The resulting highly predictive set of SNPs was combined with a probabilistic neural network algorithm to form a so-called V1b-gene test [104].

Among patients with major depression, the V1b-gene test predicted with quality criteria for sensitivity and specificity of up to 95% whether a patient with current major depression would have had a low versus high ACTH response in the dex/CRH test. Because high ACTH response is a proxy of exaggerated hypothalamic paraventricular AVP release, only patients with high ACTH response are predicted to respond favorably to V1b-antagonist treatment. Using bioinformatics, it could be demonstrated that the genotypes identified and used for the V1b- gene test are functionally related to intracellular components of AVP-V1b signaling (Müller-Myhsok, personal communication). This underscores that the genotypes used in this approach are biologically relevant as they encode important downstream factors of that specific signaling cascade.

A V1b-gene test kit can be developed as a companion diagnostic aiming to be implemented for near-patient testing, which means that the analysis can be done in clinical routine laboratories. This type of test can be applied within a few hours, assuring the rapid availability of a treatment recommendation with the capacity of the clinical routine laboratory as the sole time-restricting factor. Examples of successful implementation of such type of gene tests for near-patient testing, including approval by regulatory authorities, are test kits for diagnosing the Cytochrome P450 metabolizer status (e. g., Roche AmpliChip Cyp450 test [105]).

A V1b gene test that has good quality criteria and allows uncomplicated near-patient administration has the advantage over the complex clinical dex/CRH-test, enabling widespread use and may open for the first-time targeted use of a neuropeptide receptor antagonist, in this case, a V1b-antagonist, that works only in patients that are precisely identified with a gene-based companion test.

Conclusion

The crisis of discovery of antidepressant drugs that have innovative mechanisms of action and are more effective than those we have, seems to come to an end, which is signaled by two totally different pathways that give reason for hope:

1) Quite surprisingly, astute clinician-scientists have discovered that ketamine and some psychedelics exert rapid-acting effects in a large subgroup of depressed patients, notably also if they had failed to respond to standard antidepressant [8]. The pharmacological properties of the first antidepressants discovered in the 1950s were elaborated only after their beneficial clinical effects had been observed. Today, the situation is similar also with ketamine and psychedelics, whose known pharmacologies are very diverse, and the next step involves basic research efforts to dissect, by reverse engineering which many actions these drugs have through backward engineering, which of the many actions convey the rapid antidepressant effects and how these desired mechanisms can be separated from those which exert undesired adverse effects.

In this context, the case of ketamine, which when administered as an oral drug with prolonged release is safe, tolerable, and shows potential for clinical effectiveness, but does not produce adverse effects [106], is quite educational: ketamine is labeled as an NMDA receptor antagonist, but has many other mechanisms of action. The pharma company Allergan had discovered and developed a specific and selective NMDA receptor antagonist (Rapastinel) and had learned the hard way that this drug did not differ from placebo in primary and key secondary endpoints [107]. Now, the race is on to find the mechanism by which ketamine exerts its antidepressant effects and, if discovered, entirely innovative rapid-acting drugs become hopefully clinically available. The same applies to psychedelics, whose development is burdened by potential psychotic effects and addiction.

2) The other pathway is at the center of this paper and focuses on known or at least hypothesized pathology underlying depression of the individual patient. The drugs used here should specifically target the individual pathology related to defunct adaptation to stress. Research has to consider that the more specific one gets with a drug, the more one needs to know about the causal mechanism underlying the individual depression. Genetic, genomic, biochemical, and systemic research efforts are needed and are equally important as a new line of thought in the clinical research space integrating neuroscience-based information that ranges from polymorphisms to imaging data. It also needs to be explored if new technologies from artificial intelligence allow us to integrate these “big data” into a clinically meaningful tool. That is what it takes if one moves into the precision medicine arena. In light of these requirements, it was not surprising that specifically acting drugs like V1b- or CRHR1-antagonists did not work in patients categorically classified only according to verbal information and not by laboratory findings indicating that the individual patient has an AVP- or CRH-related pathology. It was proposed some time ago that all genetic, imaging, neuroendocrine, and other pathological data have to be integrated to allow an appraisal of the target system needed for appropriate specific intervention [4]. The present overview of the stress system focuses on the neuropeptide AVP being just one case, and other targets of the stress system are currently under scrutiny.

From a clinician scientist’s perspective, it is obvious that only close collaboration between basic and clinical researchers and also a more symptom-orientated approach together with a stepwise departure from traditional diagnostic categories will improve pharmacotherapy in psychiatry, and specifically in depression and anxiety disorders [108]. Such an endeavor will be challenging, including the massive investments needed. A global return of investment analysis by Chisholm et al. [109] estimated that the economic and health benefits of better treatments would clearly outweigh the costs needed to realize these improvements. In light of the high prevalences of anxiety disorder and depression, amounting to 4% of the global population, and considering that these disorders are important risk factors for coronary heart disease, diabetes, osteoporosis, dementia, and suicide, major improvements in drug discovery and development are an extremely urgent demand.

Conflict of Interest

F. Holsboer is the founder of HMNC Holding GmbH Munich and head of the Scientific Advisory Board. He is co-inventor of patent WO2014202541A1, “Method for predicting a treatment response to a CRHR1 antagonist and/or a V1B antagonist in a patient with depressive and/or anxiety symptoms”. M. Ising has no conflicts of interest to disclose.

Acknowledgement

We wish to thank Marius Myhsok for his assistance in preparing Fig. 1 for this manuscript.

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Correspondence

Publication History

Received: 03 May 2024

Accepted after revision: 06 June 2024

Article published online:
19 August 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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