Psychopharmacological Frontiers (1)

Psychopharmacological-Frontiers-1-Christian-Jonathan-Haverkampf-psychiatry-series

Psychopharmacological Frontiers

Christian Jonathan Haverkampf, M.D.

New developments in psychopharmacology have driven much of the progress over the last decades. This article discusses new developments in the area of antidepressants and antipsychotics.

Keywords: depression, SSRI, SNRI, ketamine, glutamate antagonist, NMDA, scopolamine, magnesium, glutamine, CP-AMPA, serotonin, norepinephrine, dopamine, antidepressants, major depressive disorder, medication, treatment psychiatry

Table of Contents

Introduction. 4

Discovery. 5

From Symptom to Etiology. 6

Animal Models. 6

Imaging Techniques. 7

Molecular Structures. 7

Phenotypic Drug Discovery. 7

Induced Pluripotent Stem Cells. 8

Genetics. 8

Antidepressants. 9

Genetics. 10

NMDA Receptor Antagonist: Ketamine. 10

Esketamine. 11

Vortioxetine. 12

Serotonin Receptor Antagonists. 12

GABA Transporter (GAT) Inhibitors. 13

σ receptor ligands. 13

Agomelatine. 13

Novel Compounds. 14

Antipsychotics. 14

Risperidone, Paliperidone, Isoperidone. 16

Brexipiprazole. 16

Cariprazine. 16

Lurasidone. 17

Experimental Compounds. 17

Flavanone derivatives. 17

Neurotensin Analogs. 18

Plants. 18

Psychedelics. 19

Psilocybin. 19

Non-traditional Medication. 19

Antidepressant Switching. 20

Conclusion. 20

References. 22

Introduction

Although many antidepressant drugs are currently available, they are far from optimal. Approximately half of patients do not respond to initial first line antidepressant treatment, while approximately one third fail to achieve remission following several pharmacological interventions. Furthermore, several weeks or months of treatment are often required before clinical improvement, if any, is reported. Moreover, most of the commonly used antidepressants have been primarily designed to increase synaptic availability of serotonin and although they are of therapeutic benefit to many patients, it is clear that other therapeutic targets are required if we are going to improve the response and remission rates. It is clear that more effective, rapid-acting antidepressants with novel mechanisms of action are required.

Clinical depression is a serious mental disorder characterized by low mood, anhedonia, loss of interest in daily activities, and other symptoms, and is associated with severe consequences including suicide and increased risk of cardiovascular events. Depression affects nearly 15% of the population. The standard of care for the last 50 years has focused on monoamine neurotransmitters, including such treatments as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs). However, these treatments have significant limitations: they can take weeks before showing mood-altering effects, and only one to two out of ten patients shows clinical effects beyond those associated with placebo.

The situation may even be worse for the antipsychotics. While many patients suffering from psychosis are helped by an antipsychotic, and many can even lead relatively normal day to day lives again, the potential side effects are frequently worse than those of the antidepressants. Also, as with the antidepressants there are many patients who only achieve a partial or in several cases only little remission.

Discovery

Between 2009 and 2016, 254 new drugs were approved. Of those, only 9 were for a psychiatric indication. (Preskorn, 2017) Research and development of drugs for psychiatric disease is currently in a state of decline. Despite the increasing prevalence and healthcare costs of psychiatric disease, the costly and unpredictable drug development process has led to decreased public and investor confidence in the abilities of companies to develop safe and efficacious drugs. (Chandler, 2013) Chandler identified the following points:

  • Costly and unpredictable drug discovery process reduces investment for psychiatric indications.
  • Unidentified pathophysiology for psychiatric disease prevents hypothesis driven research.
  • Lack of biomarkers and poor disease modelling hinder the drug development process.
  • Placebo effect reduces ability to detect symptomatic improvement from therapeutic intervention.
  • Changes in corporate culture and regulation, and more basic research will reverse these trends.

Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular.

My optimism is based partly on the extraordinary vitality of neuroscience and perhaps, even more important, on the emergence of remarkable new tools and technologies to identify the genetic risk factors for psychiatric disorders, to investigate the circuitry of the human brain, and to replace current animal models that have failed to predict efficacious new drugs that act by novel mechanisms in the brain. Based on family and twin studies, autism, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder are among the most heritable of all common medical disorders. As larger population samples are collected, progress is accelerating in the genetic dissection of schizophrenia, bipolar disorder, and autism. A list of risk-associated genes does not guarantee an understanding of disease or of new therapies. One exciting recent development is the emerging recognition that genes involved in schizophrenia, bipolar disorder, and autism do not represent a random sample of the genome. Rather, the genes are beginning to coalesce into identifiable biochemical pathways and components of familiar neural structures. More excitement comes from the finding that a large number of risk-associated genes in autism, schizophrenia, and bipolar disorder code for proteins involved in the structure and function of synapses. If other areas of medicine can guide us, there is enormous promise in deprioritizing existing drugs and old-fashioned animal-based assays as investigative tools and instead focusing on actual disease mechanisms identified by genetics. Technology has only recently begun to make this possible. (Hyman, 2013)

Populations studied have expanded diagnostically and demographically, and approved psychiatric indications have become more focused on the clinical entities actually studied, including in some cases specific symptom domains of recognized syndromes. Trial designs have become increasingly complex and informative, and approaches to data analysis have evolved to better model the reality of clinical trials. (Laughren, 2010)

From Symptom to Etiology

Drug discovery could be stimulated by designing new classification and sensitive assessment tools for psychiatric disorders, which bear closer relationships to neuropharmacological and neuroscientific developments. This is in line with the vision of precision psychiatry in which patients are clustered, not merely on symptoms, but primarily on biological phenotypes that represent pathophysiological relevant and ‘drugable’ processes. (van der Doef et al., 2018)

Animal Models

Most large pharmaceutical companies have downscaled or closed their clinical neuroscience research programs in response to the low clinical success rate for drugs that showed tremendous promise in animal experiments intended to model psychiatric pathophysiology. The adoption of a “translational-back translational strategy” for central nervous system drug discovery has been advocated involving novel application of drugs with established safety profiles in proof-of-principle studies in humans, which in turn encourage parallel studies using experimental animals to provide vital data on the neural systems and neuropharmacological mechanisms related to the actions of the candidate drugs. (Phillips, Geyer, & Robbins, 2018). While animal studies pose ethical dilemmas, it has been argued that they are essential for elucidating human psychopathology and that improving the predictive validity of animal models is necessary for developing more effective interventions for mental illness. (Kaffman, White, Wei, Johnson, & Krystal, 2019)

Imaging Techniques

The contribution of human PET and SPECT neuroreceptor occupancy studies to the understanding of drug action in psychiatric illness, and how they can aid the development of new drugs. In therapeutic drug development, these techniques may be used to assess receptor occupancy profiles, likely drug dosages and dosing intervals which cannot be reliably assessed in humans by other methods. (Talbot & Laruelle, 2002)

Molecular Structures

As for antidepressants, the authors suggest that given the long-awaited availability of credible three-dimensional structures for the SERT and related monoamine transporter proteins, cutting-edge computational methods should be the linchpin of future drug discovery efforts regarding monoamine-based antidepressant lead compounds. Because these transporter inhibitors cause a ubiquitous increase in extraneuronal neurotransmitter levels leading to side and adverse therapeutic effects, the drug discovery should extend to appropriate manipulation of the ‘downstream’ receptors affected by the neurotransmitter boost. Efficient use of new computational strategies will accelerate the drug discovery process and reduce its economic burden. (Immadisetty, Geffert, Surratt, & Madura, 2013)

Phenotypic Drug Discovery

Phenotypic drug discovery is increasingly being recognized as a viable compliment to target-based drug discovery. By measuring functional changes, typically at a systems level, phenotypic drug discovery can facilitate the identification of compounds having a desirable pharmacology. This capability is particularly important when studying CNS diseases where drug efficacy may require modulation of multiple targets in order to overcome a robust, adaptive biological system. This can involve optimizing complex behavioural features in animal models without identifying any biomolecular targets involved. (Shao et al., 2016) However, the downside is that this may involve many trial runs in animal models, which can be wasteful and ethically questionable. (Wen, Christian, Song, & Ming, 2016)

Induced Pluripotent Stem Cells

Psychiatric disorders are heterogeneous disorders characterized by complex genetics, variable symptomatology, and anatomically distributed pathology, all of which present challenges for effective treatment. Current treatments are often blunt tools used to ameliorate the most severe symptoms, often at the risk of disrupting functional neural systems, thus there is a pressing need to develop rational therapeutics. Induced pluripotent stem cells (iPSCs) reprogrammed from patient somatic cells offer an unprecedented opportunity to recapitulate both normal and pathologic human tissue and organ development and provides new approaches for understanding disease mechanisms and for drug discovery with higher predictability of their effects in humans. Here we review recent progress and challenges in using human iPSCs for modelling neuropsychiatric disorders and developing novel therapeutic strategies. (Wen et al., 2016)

Genetics

Psychiatric genetics is in an era of discovery. Genome-wide association analyses and other genomic analyses are paving the way for rapid progress in understanding the biological etiology of psychiatric disorders. Findings can improve our understanding of the mechanisms underlying treatment responses, and the identified biomarkers could eventually guide the choice of medication in patients depression, schizophrenia or other conditions.

The Psychiatric Genomics Consortium, for example, is comprehensively evaluating common single-nucleotide polymorphisms, rare variants, gene sets and pathways, and other genetic variations, to reveal the cryptic genetic and biological basis of psychiatric illnesses. Findings for key psychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, attention-deficit/hyperactivity disorder, major depression, and anorexia nervosa have been made. (Watson, Yilmaz, & Sullivan, 2020) Meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies have been performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. (Fabbri et al., 2018) In another example, a discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China that are part of the Chinese Antipsychotics Pharmacogenomics Consortium. The study authors identified genes related to synaptic function, neurotransmitter receptors, and schizophrenia risk that are associated with response to antipsychotics. (Yu et al., 2018) Yet another study investigated the potential functionality of previously implicated noncoding variants on schizophrenia treatment response and thoroughly investigated previous genome wide association studies to pinpoint variants that may play a causal role in poor schizophrenia treatment outcomes, and provides potential candidate genes for further study in the field of antipsychotic response. (Ovenden et al., 2017)

Antidepressants

Despite research efforts spanning six decades, the most prominent antidepressant drugs to date still carry several adverse effects, often serious enough to warrant discontinuation of the drug. Molecular mechanisms of depression are now better understood such that some of the specific receptors responsible can be targeted for activation or inhibition. For SSRIs, high occupancies at the serotonin transporter (SERT) are achieved at therapeutic doses, although the minimum SERT occupancy required for therapeutic response remains undefined. Previous attempts to augment the antidepressant effect of SSRIs by pindolol have generally used daily doses which result in inadequate 5-HT1A receptor occupancy. (Talbot & Laruelle, 2002)

Other promising targets for potential rapid antidepressant effects, include  (Machado-Vieira, Henter, & Zarate, 2017):

  • NMDA receptor antagonists (e.g. ketamine)
  • the cholinergic system (scopolamine)
  • the opioid system (ALKS-5461)
  • corticotropin releasing factor (CRF) receptor antagonists (CP-316,311)

Genetics

When using antidepressants, tailoring a particular medication to a specific patient is at present mostly based on clinical heuristics and trial. However, it has been shown that epigenetic biomarkers based on DNA methylation status of specific gene promoter regions, for examples, can predict the individual susceptibility toward monoaminergic drugs, psychotherapy, or electroconvulsive therapy, making it possible to provide clinicians and patients with a specific recommendation toward a certain treatment. (Frieling, Bleich, & Neyazi, 2020)

NMDA Receptor Antagonist: Ketamine

Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of major depressive disorder, and in the development of novel therapeutics for this disorder. The rapid and robust antidepressant effects of the N-methyl-d-aspartate (NMDA) antagonist ketamine were first observed in 2000. Since then, other NMDA receptor antagonists have been studied in MDD. Most have demonstrated relatively modest antidepressant effects compared to ketamine, but some have shown more favourable characteristics. (Machado-Vieira, Henter, & Zarate, 2017)

Both preclinical and clinical data show strong, rapid and sustained effects of the NMDA receptor antagonist ketamine in treatment-resistant depression. An understanding of the mechanisms underlying the rapid antidepressant effects in treatment-resistant patients by drugs such as ketamine may uncover novel therapeutic targets that can be exploited to meet the Olympian challenge of developing faster, better and stronger antidepressant drugs. (O’Leary, Dinan, & Cryan, 2015) It is important to note that ketamine, while effective in rapidly reducing depressive symptoms, is a drug that is subject to abuse and has significant side effects, raising concerns about its widespread clinical utility. (Kenwood, Roseboom, Oler, & Kalin, 2019) It has been argued that one should be cautious about widespread and repeated use of ketamine before further mechanistic testing has been performed to determine whether ketamine is merely another opioid in a novel form. (George, 2018) Other substances that have an effect on NMDA receptors may thus have a better safety profile. Data supports the potential antidepressant activity of metabotropic Glutamate 5 receptor antagonists as well as the involvement of metabotropic Glutamate 5 receptors in the pathophysiology of depression. (Palucha-Poniewiera et al., 2013)

Several signaling systems have been implicated in the mechanism of action of ketamine, including the N-methyl-D-aspartate (NMDA) receptor, the AMPA receptor, the glutamatergic system, and the opiate system. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) have also been linked to ketamine response and independently to major depression. VEGF signaling seems to play an important role in the medial prefrontal cortex in mediating the antidepressant effects of ketamine. (Kenwood, Roseboom, Oler, & Kalin, 2019) Research has demonstrated the significance of glutamatergic pathways in depression and the association of this system with the stress pathway and magnesium homeostasis. Treatment with NMDA receptor antagonists and magnesium have shown the ability to sprout new synaptic connections and reverse stress-induced neural changes, opening up promising new territory for the development of drugs to meet the unmet need in patients with clinical depression. (Zarate et al., 2013) Still, serotonin seems to play a significant role in mediating sustained antidepressant activity of ketamine. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of serotonin transmission which underlies the antidepressant response. (Gigliucci et al., 2013) Ketamine has surprisingly rapid and long-lasting effects on the recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis. (Soumier, Carter, Schoenfeld, & Cameron, 2016)

Esketamine

In a first clinical study of treatment-resistant depression, the antidepressant effect of nasal esketamine was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency(Daly et al., 2018) Preliminary data indicated in another study that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide. (Canuso et al., 2019)

Vortioxetine

Vortioxetine is a novel antidepressant with effects on multiple serotonin receptors and on the serotonin transporter. Several placebo-controlled and active-treatment studies demonstrate the antidepressant efficacy and tolerability of vortioxetine in adult patients affected with major depressive disorder  (Orsolini et al., 2017). However, there is no suggestion of superiority over active comparators. (Katona & Katona, 2014) Vortioxetine also seems to own procognitive activity. It seems generally well tolerated, without significant cardiovascular or weight gain effects. The most common adverse events reported included nausea, vomiting, hyperhidrosis, headache, dizziness, somnolence, diarrhoea and dry mouth (Orsolini et al., 2017). In a study comparing vortioxetine and mirtazapine, the former did not cause cognitive or psychomotor impairment, while the latter impaired cognitive and psychomotor performance on day two. Most of these effects disappeared after multiple doses of mirtazapine. (Theunissen et al., 2013)

Serotonin Receptor Antagonists

Serotonin 5HT3 receptors have long been identified as a potential target for antidepressants. Several studies have reported that antagonism of 5HT3 receptors produces antidepressant-like effects. 5HT3 receptors located on the serotonergic and other neurotransmitter interneuronal projections control their release and affect mood and emotional behaviour. But they may also have protective effects in the pathogenic events including hypothalamic–pituitary–adrenal-axis hyperactivity, brain oxidative stress and impaired neuronal plasticity, pointing to hereby unknown and novel mechanisms of their antidepressant action. (Gupta, Prabhakar, & Radhakrishnan, 2016)

GABA Transporter (GAT) Inhibitors

The inhibition of plasma membrane GABA transporters (GATs) is responsible for anxiolytic-like, anticonvulsant, antinociceptive and antidepressant-like effects in mice. In one study, two novel 2-substituted 4-hydroxybutanamides were studied (BM 130 and BM 131) which inhibit certain subtypes of the GABA transporter. It showed that in a mouse model BM 130 and BM 131 had anxiolytic-like, antidepressant-like and antinociceptive properties. (Sałat et al., 2013)

σ receptor ligands

A number of σ receptor ligands have been demonstrated to possess antidepressant-like effect in some experimental paradigms. In one study using the new σ1 receptor ligands PB190 and PB212 in the mouse model gave support to the hypothesis that σ1-receptors might be one of possible mechanisms by which drugs induce antidepressant-like activity and revealed that this effect may be potentiated by NMDA receptor antagonists, e.g. AMA. (Skuza et al., 2014)

Agomelatine

The antidepressant, agomelatine, acts as an agonist at melatonin MT1 and MT2 receptors and as an antagonist at serotonin 5‐HT2C receptors. In one investigation of six pooled studies, it had a significantly greater effect on anxiety symptoms than both placebo and a number of comparator antidepressants (fluoxetine, sertraline and venlafaxine). In more anxious depressed patients, agomelatine had a significantly greater effect on anxiety and depressive symptoms than both placebo and comparator antidepressants. (Stein, Picarel-Blanchot, & Kennedy, 2013)

Novel Compounds

One study indicated that two phenylpiperazine derivatives 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) possessed high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. They showed considerable antidepressant and anxiolytic effects in the mouse model. HBK-15 had stronger antidepressant-like properties, and HBK-14 displaeds greater anxiolytic-like activity. The involvement of the serotonergic system, particularly 5-HT1A receptor, appeared to play a significant role in the antidepressant and anxiolytic effects. (Pytka et al., 2015) In another study, a carborane has shown effectiveness on the P2X7 receptor (P2X7R) which can target depreesion. (Wilkinson et al., 2014)

Antipsychotics

Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. All effective antipsychotics show significant D2 receptor occupancy. However, at least for atypical antipsychotics, there is no clear relationship between occupancy and clinical response. (Talbot & Laruelle, 2002) Antipsychotic drugs come with a plethora of debilitating side effects, many of which are due to interactions with other G protein-coupled receptors other than D2. The crystal structure of D2R in complex with the antipsychotic drug risperidone has been elucidated. The structure reveals features that might be useful for the design or discovery of drugs that have greater selectivity for D2R than existing therapeutics, and consequently have fewer side effects. Data suggests that the D2R structure can regulate the kinetics of drug binding, which in turn might be associated with desirable therapeutic outcomes. The hydrophobic patch in D2R is absent in the D3R and D4R structures, presumably because of the separation between the analogous EL1 and EL2 residues in the latter two receptors. The objective is the design and discovery of D2R ligands that have higher selectivity than current antipsychotics, and potentially greater therapeutic impact. (Sibley & Shi, 2018) The low liability of some atypical antipsychotics for extrapyramidal side effects does not appear to be explained by their 5-HT2A antagonism, and the muscarinic receptor occupancy of some drugs may be partly explanatory. (Talbot & Laruelle, 2002)

About one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. (Rampino et al., 2019) Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. (Rampino et al., 2019) Repeated D2 antagonist administration downregulates spontaneously active dopamine neurons by producing overexcitation-induced inactivation of firing (depolarization block). In MAM rats, chronic D2 antagonist treatment leads to persistent DA supersensitivity that interferes with the response to drugs that target upstream pathology. (Sonnenschein & Grace, 2019)

In recent years metabotropic glutamate receptors have been investigated in schizophrenia. Agonists seem to exhibit antipsychotic-like properties in animal models of schizophrenia. However, when these compounds have been tested in human clinical studies with schizophrenic patients, results have been inconclusive. Nevertheless, it has been recently suggested that this apparent lack of efficacy in schizophrenic patients may be related to previous exposure to atypical antipsychotics. (Muguruza, Meana, & Callado, 2016) Pimavanserin is a novel 5-HT2A inverse agonist that has shown promising results for managing hallucinations and delusions in patients with PDP without worsening motor effects or orthostasis. Yet its high cost and specialty pharmacy access may limit use in clinical practice. (Bozymski, Lowe, Pasternak, Gatesman, & Crouse, 2017) Trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds seems to block psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain, and one compound may even reduce haloperidol-induced catalepsy and prevent olanzapine from increasing body weight and fat accumulation. TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. (Revel et al., 2013)

Risperidone, Paliperidone, Isoperidone

The novel antipsychotic isoperidone, a prodrug of paliperidone, itself a metabolite of risperidone, was designed to improve liposolubility for the development of poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres to achieve near zero-order release behaviour in vivo. The results confirm the superiority of long-acting release over oral administration and indicate a valuable alternative for the clinical treatment of schizophrenia. (Zhao et al., 2017)

Brexipiprazole

Brexpiprazole (Rexulti®), is a D2/3 receptor partial agonist. Brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. The authors of one study propose based on their data that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the medial prefrontal cortex, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression. (Björkholm, Marcus, Konradsson-Geuken, Jardemark, & Svensson, 2017)

Cariprazine

Cariprazine is a dopamine D3 preferring D3/D2 partial agonist with very similar dopamine receptor subtype selectivity as dopamine. It has proven efficacy in the treatment of positive and negative symptoms of schizophrenia, as well as for relapse prevention. (Simon, Czobor, Bálint, Mészáros, & Bitter, 2009) Cariprazine exerts partial agonism of dopamine D2/D3 receptors with preferential binding to D3 receptor, antagonism of 5HT2B receptors and partial agonism of 5HT1A. Currently, cariprazine is in late-stage clinical development in patients with schizophrenia and in patients with bipolar disorder, as well as an adjunctive treatment in patients with Major Depressive Disorder and drug-resistant MDD. Available evidence seems to support cariprazine efficacy in the treatment of cognitive and negative symptoms of schizophrenia. Preliminary findings suggest its antimanic activity whilst it is still under investigation its efficacy in the treatment of bipolar depression and MDD. Furthermore, the available data seems not to allow judgements about its antipsychotic potential in comparison with currently prescribed antipsychotics. (De Berardis et al., n.d.) Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine appeared effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients. (Neill et al., 2016)

Lurasidone

While lurasidone has full antagonist activity at dopamine D2 and serotonin 5-HT2A receptors, it also has high affinity for serotonin 5-HT7 receptors and is a partial agonist at 5-HT1A receptors. Long-term treatment of schizophrenia with lurasidone has been shown to reduce the risk of relapse. Lurasidone appears associated with minimal effects on body weight and low risk for clinically meaningful alterations in glucose, lipids or electrocardiogram parameters. (Loebel & Citrome, 2015)

Experimental Compounds

Flavanone derivatives

Results of in vitro and mouse model in vivo studies suggest that some novel flavanone derivatives have potential antipsychotic effects and may be useful in the treatment of schizophrenia. (Gu, Chen, Zhang, Zhang, & Li, 2017)

Neurotensin Analogs

Neurotensin (NT) analogs are known to produce antipsychotic-like effects. Vadnie and colleagues examined whether PD149163, a brain-penetrant NTS1-specific agonist, displays antipsychotic-like effects in transgenic mice by investigating the effect of PD149163 on amphetamine-mediated hyperactivity and amphetamine-induced disruption of prepulse inhibition, as well as the effect of PD149163 on glycogen synthase kinase-3 (GSK-3) activity, a downstream molecular target of antipsychotics and mood stabilizers, using phospho-specific antibodies. Results indicated that PD149163 may be a novel antipsychotic. (Vadnie et al., 2016)

Plants

Many commonly used drugs today have their origin in a plant remedy, from which the active substance against a condition was isolated. For example, in Turkish folk medicine, decoctions and infusions are prepared from the flowers of Anthemis wiedemanniana, which is used against central nervous system disorders in Turkish folk medicine. The antidepressant potentials of the extracts were evaluated in mouse models, and bioassay-guided fractionation and isolation techniques revealed tatridin A and tanachin (1-epi-tatridin B) as the main active components of the flowers. (Gürağaç Dereli, Ilhan, & Küpeli Akkol, 2018) Another example is ayahuasca, a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine and harmine, which causes effects of subjective well-being. In an open-label trial conducted in an inpatient psychiatric unit, statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after ayahuasca administration. Ayahuasca did not seem to induce episodes of mania, hypomania or psychedelic effects. (de Osório et al., 2015) In yet another study, the ethyl acetate fraction of Quercus incana yielded two new compounds. Their structural formulas were deduced to be 2-(4-hydroxybutan-2-yl)-5-methoxyphenol and 4-hydroxy-3-(hydroxymethyl) pentanoic acid. Both compounds showed anxiolytic and antidepressant effects. The effect at 30 mg/kg of the compounds was comparable to the reference drug imipramine (60 mg/kg). (Sarwar et al., 2018)

Psychedelics

Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. However, these approaches are so far highly experimental and not without risks.

Psilocybin

Acute administration of the serotonin 1A/2A/2C receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes toward positive states. Carhart-Harris and colleagues reported on the safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. Twenty patients with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment; nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months. (Carhart-Harris et al., 2018) Psilocybin also appears to be associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. The authors suggested that while SSRIs mitigate negative emotions, psilocybin may allow patients to confront and work through them. (Roseman, Demetriou, Wall, Nutt, & Carhart-Harris, 2018) Acute treatment with psilocybin seems to decrease amygdala reactivity during emotion processing, which may be associated with an increase of positive mood. Using blood oxygen level-dependent functional magnetic resonance imaging, a study found that amygdala reactivity to negative and neutral stimuli was indeed lower after psilocybin administration than after placebo administration. The psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state. (Kraehenmann et al., 2015)

Non-traditional Medication

The gut microbiome is a key component of the gut-brain axis. Gut bacteria can communicate with the brain through a variety of pathways including the hypothalamic–pituitary–adrenal axis, immune modulation, tryptophan metabolism and the production of various neuroactive compounds. Psychobiotics containing various Lactobacillus and Bifidobacterium species have demonstrated the ability to improve mood, reduce anxiety and enhance cognitive function in both healthy populations and patient groups. (Butler, Sandhu, Cryan, & Dinan, 2019)

Antidepressant Switching

Nonresponders to antidepressant monotherapy during acute treatment of major depression are often switched to a new antidepressant. However, there is is a dearth of randomized controlled trials investigating switching. There is no high-level evidence that switching the antidepressant is effective when compared to simply continuing the initial antidepressant. Since there are better treatment options than switching, physicians should be cautious to switch antidepressants. (Bschor, Kern, Henssler, & Baethge, 2018)

Conclusion

There is hope, but we are still far away from fitting the medication to the individual patient. In many cases, particularly in the primary care setting, but by no means limited to it, a favourite antidepressant or antipsychotic is used, regardless of the specific needs of the patient. On the other side, we have genetic screening for receptor variations in research settings, but also available through the internet. Unfortunately, we have not reached the point yet where we can use all this data effectively in the treatment of patients. Further insight into the neurobiology of depression and psychosis is needed, as well as a better understanding of how psychological and environmental parameters factors into the epigenesis and treatment of depression and psychosis.

Disclosure: The authors report no conflicts of interest in this work.


Dr Jonathan Haverkampf, M.D. (Vienna) MLA (Harvard) LL.M. (ULaw) BA (Dartmouth) trained in medicine, psychiatry and psychotherapy and works in private practice for psychotherapy, counselling and psychiatric medication in Dublin, Ireland. The author can be reached by email at jonathanhaverkampf@gmail.com or on the websites www.jonathanhaverkampf.com and www.jonathanhaverkampf.ie.

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