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.
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.
Stage of development
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.
Stage of development
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.

Stage of development
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
Coppen A, Shaw DM, Farrell JP. Potentiation of the antide- Conclusions
pressive effect of a monoamine-oxidase inhibitor by tryp- The clinical management of depression remains a major concern for clinicians. In fact, despite the associated bur- McClure DJ. The role of dopamine in depression. Can Psy- den and a number of therapeutic options, including non- pharmacological interventions, response rates remain Hirschfeld RM. History and evolution of the monoamine hy- low. Therefore, shifting the interest on the development pothesis of depression. J Clin Psychiatry 2000;61(Suppl 6):4-6.
of novel antidepressants beyond monoaminergic modula- Kicey CA. Catecholamines and depression: a physiological tion is attentively evaluated both by pre-clinical research- theory of depression. Am J Nurs 1974;74:2018-20.
ers and practitioners. Nonetheless, greater insights on the Nutt D, Demyttenaere K, Janka Z, et al. The other face of de- aetiology of depression are needed, along with more ac- pression, reduced positive affect: the role of catecholamines curate nosological constructs to allow a more focused ex- in causation and cure. J Psychopharmacol 2007;21:461-71.
ploration of potential novel antidepressant targets, with a Potter WZ, Manji HK. Catecholamines in depression: an up- special attention to sub-threshold bipolarity as potential, date. Clin Chem 1994;40:279-87.
insidious, responsible of “pseudo”-resistance in the phar- Sulser F, Vetulani J, Mobley PL. Mode of action of antide- macological treatment of depression 49 72.
pressant drugs. Biochem Pharmacol 1978;27:257-61.
Wade A, Friis Andersen H. The onset of effect for escitalo- References
pram and its relevance for the clinical management of de- pression. Curr Med Res Opin 2006;22:2101-10.
Terra JL. Suicide risk and depression. Rev Prat 2008;58:385-8.
Charney DS, Menkes DB, Heninger GR. Receptor sensitivity Burcusa SL, Iacono WG. Risk for recurrence in depression. and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression. Kessler RC, Berglund P, Demler O, et  al. The epidemiol- Arch Gen Psychiatry 1981;38:1160-80.
ogy of major depressive disorder: results from the Na- Werner FM, Covenas R. Classical neurotransmitters and tional Comorbidity Survey Replication (NCS-R). JAMA neuropeptides involved in major depression: a review. Int J Salzer HM, Lurie ML. Anxiety and depressive states treated Wager-Smith K, Markou A. Depression: a repair response to with isonicotinyl hydrazide (isoniazid). AMA Arch Neurol stress-induced neuronal microdamage that can grade into a chronic neuroinflammatory condition? Neurosci Biobehav Scanlon WG, White WM. Iproniazid (marsilid): its use in office treatment of depression. Am J Psychiatry Wolkowitz OM, Reus VI. Neurotransmitters, neuroster- oids and neurotrophins: new models of the pathophysiol- Kuhn R. The treatment of depressive states with G 22355 (im- ogy and treatment of depression. World J Biol Psychiatry ipramine hydrochloride). Am J Psychiatry 1958;115:459-64.
Healy D. The three faces of the antidepressants: a critical Machado-Vieira R, Baumann J, Wheeler-Castillo C, et  al. commentary on the clinical-economic context of diagnosis. The timing of antidepressant effects: a comparison of di- verse pharmacological and somatic treatments. Pharmaceu- Poe TE. Fluoxetine. A new antidepressant. N C Med J Bosker F, Vrinten D, Klompmakers A, et al. The effects of a Preskorn SH. CNS drug development. Part I: The early pe- 5-HT1A receptor agonist and antagonist on the 5-hydrox- riod of CNS drugs. J Psychiatr Pract 2010;16:334-9.
ytryptamine release in the central nucleus of the amygdala: Hanada K, Umemura S. Tricyclic antidepressants. Nippon a microdialysis study with flesinoxan and WAY 100635. Naunyn Schmiedebergs Arch Pharmacol 1997;355:347-53.
Howland RH. MAOI antidepressant drugs. J Psychosoc Cremers TI, Spoelstra EN, de Boer P, et al. Desensitisation of 5-HT autoreceptors upon pharmacokinetically moni- tored chronic treatment with citalopram. Eur J Pharmacol Owens MJ. Selectivity of antidepressants: from the monoam- ine hypothesis of depression to the SSRI revolution and be- yond. J Clin Psychiatry 2004;65(Suppl 4):5-10.
Charney DS, Heninger GR, Sternberg DE, et al. Presynap- tic adrenergic receptor sensitivity in depression. The effect Ferguson JM. SSRI Antidepressant medications: adverse ef- of long-term desipramine treatment. Arch Gen Psychiatry fects and tolerability. Prim Care Companion J Clin Psychia- Stahl S, editor. Stahl’s Essential Psychopharmacology. Third Schildkraut JJ. The catecholamine hypothesis of affective Edition. San Diego, CA: Cambridge University Press 2008.
disorders: a review of supporting evidence. Am J Psychiatry Payne JL, Quiroz JA, Zarate CA, Jr, et al. Timing is every- M. Fornaro
thing: does the robust upregulation of noradrenergically Blier P. The well of novel antidepressants: running dry. J regulated plasticity genes underlie the rapid antidepressant effects of sleep deprivation? Biol Psychiatry 2002;52:921-6.
Fornaro M, Giosue P. Current nosology of treatment resist- Sonawalla SB, Fava M. Severe depression: is there a best ant depression: a controversy resistant to revision. Clin Pract approach? CNS Drugs 2001;15:765-76.
Lam RW, Kennedy SH, Grigoriadis S, et al.; Canadian Net- Sheehan DV, Croft HA, Gossen ER, et al. Extended-release work for Mood and Anxiety Treatments (CANMAT). Cana- trazodone in major depressive disorder: a randomized, dou- dian Network for Mood and Anxiety Treatments (CANMAT) ble-blind, placebo-controlled study. Psychiatry (Edgmont) clinical guidelines for the management of major depressive disorder in adults. III. Pharmacotherapy. J Affect Disord Pae CU. Desvenlafaxine: a new antidepressant or just an- other one? Expert Opin Pharmacother 2009;10:875-87.
Cascade E, Kalali AH, Kennedy SH. Real-world data on Adell A. Lu-AA21004, a multimodal serotonergic agent, for SSRI antidepressant side effects. Psychiatry (Edgmont) the potential treatment of depression and anxiety. IDrugs Dell’Osso B, Bareggi SR, Palazzo MC, et al. Dai composti Howland RH. Vilazodone: another novel atypical anti- ad azione duale a quelli a triplice azione: considerazioni depressant drug. J Psychosoc Nurs Ment Health Serv sullo sviluppo di una nuova classe di antidepressivi. Giorn Feiger AD, Heiser JF, Shrivastava RK, et al. Gepirone extend- Miller AH. Neuroendocrine and immune system interac- ed-release: new evidence for efficacy in the treatment of ma- tions in stress and depression. Psychiatr Clin North Am jor depressive disorder. J Clin Psychiatry 2003;64:243-9.
de Paulis T. Drug evaluation: PRX-00023, a selective Fornaro M, Prestia D, Colicchio S, et  al. A systematic, 5-HT1A receptor agonist for depression. Curr Opin Investig updated review on the antidepressant agomelatine focus- ing on its melatonergic modulation. Curr Neuropharmacol Bermack JE, Debonnel G. Effects of OPC-14523, a com- bined sigma and 5-HT1a ligand, on pre- and post-synaptic 5-HT1a receptors. J Psychopharmacol 2007;21:85-92.
Catena Dell’Osso M, Bellantuono C, Consoli G, et  al. In- flammatory and neurodegenerative pathways in depression: Lifschytz T, Segman R, Shalom G, et al. Basic mechanisms a new avenue for antidepressant development? Curr Med of augmentation of antidepressant effects with thyroid hor- mone. Curr Drug Targets 2006;7:203-10.
Pariante CM, Lightman SL. The HPA axis in major depres- Lucas MC, Weikert RJ, Carter DS, et al. Design, synthesis, sion: classical theories and new developments. Trends Neu- and biological evaluation of new monoamine reuptake in- hibitors with potential therapeutic utility in depression and pain. Bioorg Med Chem Lett 2010;20:5559-66.
Chopra K, Kumar B, Kuhad A. Pathobiological targets of de- pression. Expert Opin Ther Targets 2011;15:379-400.
Marks DM, Pae CU, Patkar AA. Triple reuptake inhibitors: the next generation of antidepressants. Curr Neuropharma- Gobbi G, Blier P. Effect of neurokinin-1 receptor antago- nists on serotoninergic, noradrenergic and hippocampal neurons: comparison with antidepressant drugs. Peptides Kamiyama H, Matsumoto M, Otani S, et  al. Mechanisms underlying ketamine-induced synaptic depression in rat hip- pocampus-medial prefrontal cortex pathway. Neuroscience Blier P, Gobbi G, Haddjeri N, et al. Impact of substance P receptor antagonism on the serotonin and norepinephrine Wulsin AC, Herman JP, Solomon MB. Mifepristone de- systems: relevance to the antidepressant/anxiolytic re- creases depression-like behavior and modulates neuroen- sponse. J Psychiatry Neurosci 2004;29:208-18.
docrine and central hypothalamic-pituitary-adrenocortical Madaan V, Wilson DR. Neuropeptides: relevance in treat- axis responsiveness to stress. Psychoneuroendocrinology ment of depression and anxiety disorders. Drug News Per- Breuer ME, van Gaalen MM, Wernet W, et al. SSR149415, a Mansvelder HD, Mertz M, Role LW. Nicotinic modulation non-peptide vasopressin V1b receptor antagonist, has long- of synaptic transmission and plasticity in cortico-limbic cir- lasting antidepressant effects in the olfactory bulbectomy-in- cuits. Semin Cell Dev Biol 2009;20:432-40.
duced hyperactivity depression model. Naunyn Schmiede- Elgamal S, MacQueen G. Galantamine as an adjunctive bergs Arch Pharmacol 2009;379:101-6.
treatment in major depression. J Clin Psychopharmacol Davies J, Evans RH, Herrling PL, et al. CPP, a new potent and selective NMDA antagonist. Depression of central Ghaemi SN, Sachs GS, Chiou AM, et al. Is bipolar disorder neuron responses, affinity for [3H]D-AP5 binding sites on still underdiagnosed? Are antidepressants overutilized? J Af- brain membranes and anticonvulsant activity. Brain Res Beyond monoamines towards the development of novel antidepressants
Jordan GR, McCulloch J, Shahid M, et  al. Regionally se- antidepressant potential of the selective beta3 adrenoceptor lective and dose-dependent effects of the ampakines Org agonist amibegron in an animal model of depression. Phar- 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradi- Stahl SM. The sigma enigma: can sigma receptors provide ography. Neuropharmacology 2005;49:254-64.
a novel target for disorders of mood and cognition? J Clin Kalueff AV, Nutt DJ. Role of GABA in anxiety and depres- sion. Depress Anxiety 2007;24:495-517.
Naidu PS, Varvel SA, Ahn K, et al. Evaluation of fatty acid Borsook D, Richardson GS, Moore-Ede MC, et  al. GABA amide hydrolase inhibition in murine models of emotional- and circadian timekeeping: implications for manic-depres- ity. Psychopharmacology (Berl) 2007;192:61-70.
sion and sleep disorders. Med Hypotheses 1986;19:185-98.
Chen CY, Tzeng NS, Chen YC. Maintenance therapy of Nurnberg HG, Seidman SN, Gelenberg AJ, et al. Depres- celecoxib for major depression with mimicking neuropsycho- sion, antidepressant therapies, and erectile dysfunction: logical dysfunction. Gen Hosp Psychiatry 2010;32:647 e7-9.
clinical trials of sildenafil citrate (Viagra) in treated and untreated patients with depression. Urology 2002;60(Sup- Fornaro M, Aguglia E, Dell’Osso L, et al. Could the underesti- mation of bipolarity obstruct the search for novel antidepres- Overstreet DH, Stemmelin J, Griebel G. Confirmation of sant drugs? Expert Opin Pharmacother 2011;12:2817-31.


Microsoft word - spa_jul_20__11.doc

Daily Newsletter 20 Jul, 2011 Morning Glance Equity Research Desk Market Summary The market closed on a negative note on Tuesday. The overall market breadth was positive, around 57.2% of shares advanced on BSE and 59.4% of shares advanced on NSE. Out of the total 3,004 shares traded at BSE, 1,652 advanced, 1,219 declined, while 133 remained unchanged. After a lackluster morn

Microsoft word - 3. medication declaration form - information sheet 2011.doc

MEDICATION DECLARATION FORM INFORMATION SHEET THE World Anti Doping Agency (WADA) has determined that some medication may confer an unfair competitive advantage and have issued a list of those drugs and other agents that are banned by competitors. Some agents on this banned list may be used for specific medical conditions and, in some instances; the drug is the only one, which is effective.

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