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Original article • Articolo originale
Beyond monoamines towards the development of novel antidepressants
Oltre le monoamine al fine di sviluppare nuovi farmaci antidepressivi 1 Department of “Scienze della Formazione”, University of Catania, Italy; 2 Department of Psychiatry, Veteran Affairs (VA) Hospital, University of California (UCSD), La Hoya, San Diego, CA, USA ated giving priority to RCTs and meta-analyses. At present, the pharmacological management of depression appears is Objective
characterized by a wide variety of different augmentation or Herein, a concise review is presented on the current and most switching approaches (Fig.  1). Nonetheless, response rates promising antidepressant pharmacological agents for manage- remain substantially unsatisfactory, thus prompting for the development of novel agents with different mechanisms of Materials and methods
A PubMed search (1966 - February 2012) was performed using Conclusions
the following keywords or their combination: “depression”; Shifting the interest for novel antidepressant drugs beyond the “major depressive disorder”: “antidepressants”; “novel antide- monoaminergic modulation represents (Tables I-III) an intriguing pressant targets”; “monoamine”; “novel antidepressants”. Ad- opportunity to enhance response rates of depression, although ditional literature sources, including most authoritative and up- other issues, including revision of current nosological bounda- dated edited books or pamphlets were examined accordingly. Results
Key words
All relevant literature sources written in English were evalu- Monoamines • Antidepressant drugs • Novel targets Introduction
high priority of pharmaceutical companies 7. The situation changed in 1988, when the introduction of fluoxetine, a Depression is one of the most prevalent psychiatric selective serotonin reuptake inhibitor (SSRI) approved for disorders, and has unfavourable prognosis with con- the treatment of major depressive disorder (MDD) 8, alter- siderable suicide risk 1. Its lifetime prevalence rate in the United States is estimated to be 16.6%, affecting natively generically labelled as “depression”, marked the over 30 million people, with more than 80% of these beginning of a “golden era” of the pharmacological treat-individuals experiencing recurrent episodes 2 3. None- ment of the disorder 9. In fact, although not as effective as theless, despite the clinical and social relevance of the the previously introduced tricyclic antidepressants (TCAs) phenomenon, depression still faces considerable unsat- and monoamine oxidase inhibitors (MAO-Is) 10 11, the SS- isfactory response rates, thus soliciting the exploration RIs and the latter introduced classes of antidepressants, of novel therapeutic targets to develop more effective still ensured substantial remission rates compared to pla-interventions.
cebo while providing a better tolerability profile (although Concerning the pharmacological treatment of depres- not completely devoid of side-effects), thus contributing sion, currently the cornerstone of clinical management, to the widespread pharmacological management of de-numerous agents from different classes have been pro- pression 12 13. Nonetheless, the need for higher response posed since the 1950s, when the mood-enhancing prop- rates for the antidepressant treatment solicited the intro- erties of two anti-tuberculosis agents, isoniazid and ip- duction of novel compounds as well the implementation roniazid 4 5 and imipramine, also a tricyclic compound 6 of enhanced augmentation or switching strategies for cur-were serendipitously observed. Unfortunately, at that time rently available drugs.
the number of people diagnosed with “depression” who In this review, the prominent pharmacological opportu-would benefit from these “new” agents was very low, nities for the treatment of depression are briefly outlined, so that the development of antidepressants was not the focusing on novel non-monoaminergic compounds.
Correspondence
Michele Fornaro, via Teatro Greco 84, 95100 Catania, Italy • Tel. +39 347 4140003 • Fax +39 010 3537681 • E-mail: [email protected]
Journal of Psychopathology 2012;18:226-233 Beyond monoamines towards the development of novel antidepressants
Materials and methods
As a major implication, this possibility has suggested that other antidepressant targets should be explored.
Considered sources included all PubMed results written in English (updated to February 2012) systematically re-trieved using the following keywords or their combina- The need for novel antidepressant drugs:
tion: “depression”; “major depressive disorder”: “antide- the increasingly crowded antidepressant
pressants”; “novel antidepressant targets”; “monoamine”; scenario
“novel antidepressants”. Additional literature sources, in- Both pharmacological and clinical considerations con- cluding most authoritative and updated edited books or cerning the efficacy, safety, tolerability and costs influ- pamphlets were evaluated accordingly.
ence compliance and outcome of the depressed patient, soliciting novel antidepressant interventions.
The need for an anticipated onset of action
Two hundred and eighty nine randomized clinical tri- A lag phase of at least 3-4 weeks prior to the onset of an als (RCTs) or meta-analyses were assessed, while non- antidepressant effect is commonly seen with current anti- controlled studies were used only when controlled data depressant drugs 27, in contrast with an almost immediate unavailable. Finally, studies performed in humans were increase in monoamine extracellular levels evident just prioritized, while pre-clinical or animal investigations have been cited only in the absence of corresponding At least two types of 5-HT auto-receptors are present on the serotonergic neuron. Activation of 5-HT1A recep-tors, present in the somatodendritic area, reduces neu- The monoamine hypothesis of depression
ronal firing, resulting in less serotonin release from the and beyond
axon terminal. On the other hand, activation of 5-HT1B receptors causes direct inhibition of serotonin release. Since its first conceptualization,  14-16 the “monoamine 5-HT1A is also related to control of serotonergic release hypothesis of depression” largely influenced the devel- through a large feedback loop from terminal to the cell opment of novel antidepressant drugs and prescribing body region 28. It is likely that these auto-restraining proc- attitudes of clinicians toward MDD 17. This hypothesis esses counteract the initial effect of SSRIs as well as other essentially focuses on increasing the levels and syn- classes of antidepressant drugs that primarily act by sero- aptic effects of three monoamines, namely dopamine tonergic modulation, and chronic administration of these (DA), norepinephrine (NE) and the indole amine 5-hy- agents is reported to desensitize both presynaptic and droxytryptamine (5-HT) or serotonin, to induce an anti- depressant response 18-20. Within the past decades, this Similarly, complex pre- and post-synaptic modulations hypothesis has undergone extensive revision, leading to concern norepinephrinergic modulation. The alpha-2 the observation that such synaptic modifications would norepinephrinergic auto-receptors, located both on ax- be due to blockade of monoamine transporters, includ- on terminals and cell bodies, establish an effective self- ing the dopamine transporter (DAT), the norepinephrine regulation system similar to that in serotonergic neurons, transporter (NET) and the serotonin transporter (SERT) 19. which is also believed to become supersensitive during However, monoamine levels can increase rapidly fol- depression 30, while the beta-adrenoceptors are located lowing blockade of these transporters, much earlier than post-synaptically. Up-regulation of these receptors has onset of clinical action, if ever 21 22. The “neurotransmit- been observed in the course of depression, whereas ter receptor sensitivity hypothesis” of depression can down-regulation of these latter has been related to anti- explain this lag phase 23, and is also in agreement with depressant activity 31. Nonetheless, despite the discovery the neurotransmitter receptor hypothesis focusing on the of the mechanisms held to be responsible, overcoming abnormal up-regulation of receptors during the course of the lag phase of antidepressant drugs remains an unad- depression 24. Nonetheless, it is likely that modifications in receptor number and/or sensitivity following antide-pressant treatment require alterations in gene expression, The need for more effective antidepressants:
transcription, translation and production of various neu- beyond the SSRIs
rotrophic factors as the brain derived neurotrophic factor (BDNF) 25 26. Thus, in addition to modulating monoam- The SSRIs are still the most commonly prescribed antide- ine and receptor levels, the final common pathway of all pressant drugs 13. Nonetheless, their efficacy has highly antidepressants should involve the regulation of various debated, especially for most severe cases of depression 33, trophic factors, rather than just the monoamine balance.
which have favoured the use of serotonin norepinephrine M. Fornaro
FIguRe 1.
Switching and augmentation of strategies are part of routine
psychopharmacological practice of the treatment of depression,
especially for less responsive cases. Other optimizations include
the development of novel formulations of older medications to
enhance tolerability and compliance (e.g. controlled release
formulation of trazodone with milder anti-alpha-1 effect is
waiting approval for a new high-dose, 300-450 mg once-daily
formulation; similarly, desvenlafaxine, the main metabolite
of venlafaxine, under-metabolized by the kidney, appears to
have the antidepressant effects of its parent compound with a
more favourable pharmacokinetic profile) 50 51. More selective
serotonergic antidepressants are also being considered, including
the following: Lu AA21004, a SSRI with anti-nausea and anti-
anxiety 5-HT3 antagonism plus 5-HT1A action 52, vilazodone or
SB 659746A acting as SSRI/5-HT1A partial agonist 53, gepirone
ER and PRX 00023 as 5-HT1A partial agonists 54 55, VPI 013 or
OPC 14523 acting as a sigma-1/5-HT1A partial agonist 56, TGW-
00-AD/AA as 5-HT1A agonist and 5-HT2A antagonist, TGBA-
01-AD as SRI/5-HT2/5-HT1A/5-HT1D modulator, elzasonam as
5-HT1B/D antagonist 31 and agomelatine acting as 5-HT2C and
weak 5-HT2B antagonist and MT1/MT2 melatonergic agonist 38.
Additional 5-HT1A/5-HT1B modulation could be provided
by non-antidepressant augmentation strategies, including the
following: the beta-blocker pindolol acting as 5-HT1A partial
agonist and the thyroid hormone triiodothyronine (T3) modulating 5-HT1B receptors 57 as well as some triptans providing 5-HT1A and/or 5-HT1D and/or 5-HT1F agonist effects. Many more agents, including 5-HT2C/5-HT2A blockers, lithium and atypical antipsychotics are under consideration 31. Le strategie di passaggio o di aggiunta sono parte della prassi psicofarmacologica antidepressiva, specie nei casi meno responsivi. Altre strategie di ottimizzazione riguardano lo sviluppo di nuove formulazioni di vecchi farmaci allo scopo di aumentarne la tollerabilità e quindi l’aderenza al trattamento (es. formulazioni a rilascio controllato di trazodone, con minor effetto anti-alfa1 è in attesa dell’approvazione per la nuova formulazione a dosaggio elevato, 300-450 mg una volta al giorno; parimenti, la desvenlafaxina, il principale metabolita della venlafaxina, sotto-metabolizzata dal rene, pare mantenere lo stesso effetto antidepressivo del farmaco sorgente ma con un profilo farmacocinetico più favorevole) 50 51. Altri farmaci selettivi serotoninergici sono ugualmente oggetto di considerazione, inclusi i seguenti: Lu AA21004, un SSRI con attività anti-nausea ed anti-ansia legate all’antagonismo 5-HT3 più azione 5-HT1A 52, vilazodone o SB 659746A attivo quale SSRI parziale agonista 5-HT1A 53, gepirone a rilascio esteso e PRX 00023 quali parziali agonisti 5-HT1A 54 55, VPI 013 o OPC 14523 agente quale parziale agonista sigma-1/5-HT1A 56, TGW-00-AD/AA come 5-HT1A agonista e 5-HT2A antagonista, TGBA-01-AD quale modulatore SRI/5-HT2/5-HT1A/5-HT1D, elzasonam come 5-HT1B/D antagonista 31 ed agomelatina agente come antagonista 5-HT2C e blando bloccante 5-HT2B nonché come agonista melatoninergico MT1/MT2 38. L’ulteriore modulazione 5-HT1A/5-HT1B potrebbe esser fornita inoltre da strategie di “augmentation” con farmaci non antidepressivi, tra cui i seguenti: il beta-bloccante pindololo che agisce come parziale agonista 5-HT1A e l’ormone tiroideo Triiodotironina (T3) che modula I recettori 5-HT1B 57 come pure alcuni triptani che forniscono effetti di agonismo 5-HT1A e/o 5-HT1D e/o 5-HT1F. Molti altri agenti, inclusi i bloccanti 5-HT2C/5-HT2A, litio e antipsicotici atipici sono anch’essi considerati 31. reuptake inhibitors (SNRIs) such as duloxetine and ven- antidepressant drugs include targeting specific monoam- lafaxine, characterized by a more comprehensive phar- ine receptors or “tweaking” the posology of current drugs macological profile and higher antidepressant efficacy in most cases 34. Efficacy and tolerability concerns have par-tially shifted prescribing patterns towards novel pharma- When “two is not enough”: triple reuptake
cological agents, including the norepinephrine selective inhibitors
serotonin sntagonists (NaSSA) mirtazapine, or dopamin- Dual reuptake inhibitors offered clinicians effective and ergic modulators such as the norepinephrine dopamine patient-oriented SSRIs alternatives, substantially reducing reuptake inhibitor (NDRI) bupropion. These aim to en- the need for TCAs or MAO-Is and their unpleasant anti- hance the anhedonic, cognitive, metabolic and sexual cholinergic and anti-histaminergic side effects or even profile of depression frequently seen as part of disease or potentially life-threatening complications. Nonetheless, response rates did not increase to a satisfactory level, thus Additional strategies to enhance the efficacy of current suggesting further strengthening of the antidepressant Beyond monoamines towards the development of novel antidepressants
TaBle I.
Sample triple reuptake inhibitors proposed for MDD 58 59. Esempio di triple del reuptake della serotonina proposte per MDD 58 59.
Compound
Stage of development
Mechanism
TRI and specific 5-HT2C, 5-HT3, 5-HT2A, alpha1 modulator TRI and specific 5-HT2A, alpha1 and 5-HT6 modulator pharmacological profile by concomitant administration Beyond monoamines: present and future
of multiple antidepressants with different mechanisms of directions
action or by the development of novel, triple reuptake Depression has been conceptualized as the clinical inhibitors (TRIs) enhancing transmission of 5-HT, NE and expression of a broader “stress” condition underlined by immune and neuroendocrine imbalances  37, thus Remarkably, no TRI is currently available for prescrip- further shifting the interest for novel potential antide- tion over the counter either in Europe neither in the US pressant targets beyond monoamines (Table II). This is (Table I), and the expectations toward these novel agents confirmed by the recent clinical interest toward ago- still await clinical confirmation. What might be expected, melatine, acting both as 5-HT2C antagonist and as a however, is a reduced need for augmentation therapies melatonergic (MT) type I and type II agonist 38, as well and total number of daily medications, lower potential as and increasing attention toward anti-oxidative stress for pharmacokinetic interactions and, finally, better pa- modulators and pro-inflammatory cytokines. Rebal- ance of an overactive hypothalamic-pituitary-adrenal TaBle II.
Examples of novel HPA modulators being considered for MDD 31 60-62. Esempi di nuovi modulatori HPA considerati per MDD 31 60-62.
Compound
Stage of development
Mechanism
Corticotropin releasing factor-1 receptor (CRF1) antagonist Schering Plough SCH 900635 (org34517) Phase II M. Fornaro
(HPA) axis and subsequent glucocorticoid receptor Discussion
(GRs) overstimulation 39, commonly found in course of Since the introduction of newer antidepressant drugs in depression 40, via corticotropin releasing factor (CRF) 1 the past decade, there has been an increase in the diag- receptor (CRF1) antagonists 41 also represents a prom- nosis and treatment of MDD, perhaps in part related to ising opportunity to the development of novel non- the introduction of “treatments for the diagnosis”, “treat- monoaminergic antidepressants. In addition to CRF, ment-oriented observation bias” or Klerman’s “pharma- vasopressin (V) is also involved in regulating HPA axis cocentric view of the world” 47. Nonetheless, with the activity, with its b1 receptors positively stimulating exception of agomelatine 38, yet still characterized by a adrenocorticotropic hormone (ACTH) release induced substantial serotonergic activity eventually accounting by CRF, thus suggesting a Vb1 antagonist may be useful for most of its antidepressant effects, innovative non- monoaminergic antidepressants are still lacking, and Besides HPA modulators, the central nervous system most of the needs for the treatment of major depression (CNS) peptide neurokinin (NK) substance P (SP) recep- remain unmet, especially concerning residual symp- tors (SN ) are also potential antidepressant targets. In tomatology and the subsequent risk for recurrence and/ fact, since NK1 antagonists may increase 5-HT trans- mission, decreasing 5-HT1A auto-receptors sensitivity Moreover, the antidepressants that already reached the in the dorsal raphe nucleus, this would induce tonic market were produced in the early 1990s and subsequent- stimulation of hippocampal 5-HT1A post-synaptic re- ly redeveloped. There are several reasons why the field has ceptors 42 43, thus their antidepressant role is being con- been in a relative drought 48. The first problem that arose sidered especially for the painful somatic and emotional in the 1990s was the eagerness of industry to get their can- symptoms often present during the course of depres- didate antidepressants quickly to market at the expense of sion 44. The need for better management of depression performing solid pivotal trials. A second problem persist- has also renewed interest in acetylcholine (Ach) mod- ing in the field is the inadequate dosing of the candidate ulators for commonly associated cognitive symptoms. compounds in clinical trials. A third difficulty is the limited Ach transmission is negatively regulated by Ach esterase period of patent protection, especially in the presence of (AchE), which metabolizes acetylcholine into choline; financial drain exerted by generic medications. On one nicotinic receptors expressed by DA neurons at the hand, industry has to be kept in check to ensure that novel ventral tegmental area increase the responsiveness of medications are not sold at exorbitant prices, still making DA system to reward-related stimuli 45, therefore, AchE enough profits to ensure that their pipelines are not de- inhibitors as galantamine  46 and similar future agents pleted. Additionally, the cost to bring an antidepressant to should also have a place in the antidepressant arma- market is massive, and on occasion medications have to mentarium. Further focusing on the cognitive symptoms be discontinued due to unexpected adverse events even of depression, N-methyl-D-aspartate (NMDA) and al- after they have become “blockbuster”.
pha-amino-3-hydroxy-5-methyl-4-isoxazole propionic Shifting the targets of novel antidepressant drugs toward the acid (AMPA) glutamate receptors have been considered modulation of monoamine is therefore an ambitious goal as potential antidepressant targets (Table III).
from pharmacological, clinical and financial standpoints.
TaBle III.
Examples of nonmonoaminergic, non-HPA-ergic modulators proposed for MDD 63-71. Esempi di non monoaminergici, non HPA-
ergici modulatori proposto per la MDD 63-71.
Compound
Stage of development
Mechanism
Enhancers of sleep and anxiety proposed as SSRI augmentation strategies for MDD Enhancers of sexual impairment during course of MDD Beyond monoamines towards the development of novel antidepressants
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