serotonin reuptake inhibitors; the corner stone in treatment of depression for half a century – a...

2006, Vol. 6, No. 17 1799

Editorial

Neurotransmitter transporters can be divided into two types: the vesicular transporters mediating the uptake and storage of

neurotransmitters in vesicles in the presynaptic terminal and two families of membrane-bound transporters responsible for the

transport of neurotransmitters from the synaptic cleft back into the presynaptic terminal or glia cells. One of these families, the

Na+/Cl--dependent transporters, contains transporters mediating the synaptic reuptake of the monoamines norepinephrine,

dopamine and serotonin and the major inhibitory neurotransmitters g-aminobutyric acid (GABA) and glycine, and othertransporters in this family have creatine, taurine and proline as their substrates. The other transporter family consists of five

Na+-dependent excitatory amino acid transporters responsible for the synaptic reuptake of glutamate, the major excitatory

neurotransmitter in the mammalian CNS.

Being essential regulators of the synaptic activity in these important neurotransmitter systems, the membrane-bound

neurotransmitter transporters constitute highly interesting targets for pharmacological intervention in a wide range of

psychiatric and neurological disorders. Drugs targeting transporters are already being administered in the clinic for depression,attention-deficit hyperactivity disorder (ADHD), obesity and epilepsy and as smoking cessation aids. The present issue ofCurrent Topics in Medicinal Chemistry is focused on medicinal chemistry and pharmacology aspects of ligands targetingmembrane-bound neurotransmitter transporters and the possibilities and challenges in connection with the development of

novel drugs acting at these transporters or the improvement of already existing ones.

The serotonin transporter (SERT) is the key molecular target in the treatment of depression and is thus by far the most

successful drug target amongst the neurotransmitter transporters. Selective serotonin reuptake inhibitors (SSRIs) hold

significant advantages to older classes of antidepressants, in particular when it comes to their relatively mild side effects.

However, the obvious clinical benefits of SSRIs are hampered by their characteristic slow onset of action and the fact that a

considerable fraction of depression patients are non-responders to SSRI therapy. In the first review of this issue Moltzen and

Bang-Andersen outline the add-on and augmentation strategies currently being pursued in the industry to address these

problems through the development of compounds combining SERT inhibition with activities at other monoamine transporters

or at various different neurotransmitter receptors [1].

The dopamine transporter (DAT) is a potentially interesting target for a wide range of neurodegenerative and psychiatric

disorders, and furthermore it is the key mediator of the psychostimulant effects of recreational drugs such as amphetamine and

cocaine. Runyon and Carroll summarize the findings in recent structure-activity studies of 3-phenyltropane, 1,4-

dialkylpiperazine, phenylpiperidine and benztropine analogs as well as other classes of DAT ligands [2]. Furthermore, the

authors outline the results from studies of DAT inhibitors in non-human primate models of psychostimulant abuse, Parkinsons

Disease and ADHD.

In their review of monoamine transporter substrates Rothman and Baumann elucidate how the basic inhibitor/substrate

properties and the NET/DAT/SERT selectivity profile of the psychostimulant drug determine its pharmacological effects,

including its therapeutic potential and its abuse liability [3]. Since equipotent DAT/SERT substrates do not appear to induce the

cardiovascular side-effects caused by clean serotonin releasers or the psychostimulant side-effects and abuse liabilities

characteristic for clean dopamine releasers, the authors propose these ligands as candidate drugs for the treatment of cocaine

abuse.

The GABA and glycine transporters have not attracted nearly as much medicinal chemistry attention as the monoamine

transporters. In their review of the GABA transporter (GAT) field, Clausen and colleagues present the structure-activity

relationships for different series of conformationally restricted GAT ligands and propose a pharmacophore model for the GAT1

subtype [4]. Several selective GAT1 inhibitors have been published, whereas no truly selective pharmacological tools have

been identified for the other three GAT subtypes. Considering the clinical administration of the GAT1-inhibitor tiagabine in

epilepsy and the well-established therapeutic potential in augmentation of GABAergic neurosignalling in other disorders like

anxiety, convulsive states, pain and sleeping disorders these three subtypes could be interesting as drug targets as well.

1800 Current Topics in Medicinal Chemistry, 2006, Vol. 6, No. 17 Editorial

In addition to having glycine, the co-agonist of the NMDA receptors, as its substrate, the glycine transporter subtype 1

(GlyT1) is co-localized with these receptors in several CNS regions. In keeping with the glutamate/NMDA dysfunction

hypothesis of schizophrenia, inhibition of GlyT1 and the resulting augmentation of NMDA receptor signaling have been

proposed as an alternate way to treat this disorder. Kinney and coworkers present a selection of the sarcosine and non-sarcosine

based GlyT1 inhibitors published to date and outline the performances of these ligands in in vivo models for schizophrenia [5].

The major excitatory neurotransmitter glutamate plays key roles in a wide range of processes in the CNS, and an exhaustive

numbers of ligands acting at ionotropic and metabotropic glutamate receptors have been published over the years. In the last

review of this issue, Dunlop and Butera outline the relatively limited medicinal chemistry work done in the field of excitatory

amino acid transporters (EAATs) [6]. While the therapeutic potential in EAAT inhibitors may be limited, some b -lactam

antibiotics have recently been shown able to increase expression levels of EAAT proteins and have displayed promising

neuroprotective effects in various in vitro and in vivo models.

I would like to thank all the authors for their enthusiasm and dedication in contributing to this CTMC issue, and the

insightful suggestions and constructive criticism of the reviewers are also thankfully acknowledged. I hope this issue will be an

inspiring read for the scientist engaged in the neurotransmitter transporter area and that it also will serve as an introduction to

this exciting field of research for the general reader.

REFERENCES

[1] Moltzen, E. K.; Bang-Andersen, B. Serotonin reuptake inhibitors: The corner stone in treatment of depression for half a century A medicinalchemistry survey. Curr. Topics Med. Chem. 2006, 6(17), 1801-1823.

[2] Runyon, S. P.; Carroll, F. I. Dopamine transporter ligands: Recent developments and therapeutic potential. Curr. Topics Med. Chem. 2006, 6(17),1825-1843.

[3] Rothman, R. B.; Baumann, M. H. Therapeutic potential of monoamine transporter substrates. Curr. Topics Med. Chem. 2006, 6(17), 1845-1859.[4] Hg, S.; Greenwood, J. R.; Madsen, K. B.; Larsson, O. M.; Frlund, B.; Schousboe, A.; Krogsgaard-Larsen, P.; Clausen, R. P. Structure-activity

relationships of selective GABA uptake inhibitors. Curr. Topics Med. Chem. 2006, 6(17), 1861-1882.[5] Lindsley, C. W.; Wolkenberg, S. E.; Kinney, G. G. Progress in the preparation and testing of glycine transporter type-1 (GlyT1) inhibitors. Curr.

Topics Med. Chem. 2006, 6(17), 1883-1896.[6] Dunlop, J.; Butera, J. A. Ligands targeting the excitatory amino acid transporters (EAATs). Curr. Topics Med. Chem. 2006, 6(17), 1897-1906.

Anders A. Jensen, Ph.D.Department of Medicinal Chemistry

The Danish University of Pharmaceutical SciencesUniversitetsparken 2

DK-2100 CopenhagenDenmark

Email: [email protected]

Current Topics in Medicinal Chemistry, 2006, 6, 1801-1823 1801

1568-0266/06 $50.00+.00 2006 Bentham Science Publishers Ltd.

Serotonin Reuptake Inhibitors: The Corner Stone in Treatment ofDepression for Half a Century A Medicinal Chemistry Survey

Ejner K. Moltzen* and Benny Bang-Andersen

Medicinal Chemistry Research, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby-Copenhagen, Denmark

Abstract: Inhibition of serotonin (5-HT) reuptake has been a central theme in the therapy of depression for half a century.Through the years these therapies have improved, particularly with regard to side effects, and todays selective serotoninreuptake inhibitors (SSRIs) constitute a reasonably effective offer for the patients. However, there is still room for majorimprovement and considering that almost 20% of the population in the western world will experience a depressive periodin their lifetime, there is a large need for improved therapies. A large spectrum of targets and strategies are currently beingpursued, but so far none of these new approaches have been successful, mainly due to lack of a deeper understanding ofthe disease biology.

Since inhibition of 5-HT reuptake ensures a certain degree of antidepressant efficacy, there has been a large interest invarious combinations with serotonin reuptake inhibitors (SRIs) in order to improve on the shortcomings of treatment withSSRIs. Some of these approaches have resulted in marketed antidepressants, eg combinations of SRI with norepinephrine(NE) reuptake inhibition, whereas other approaches are still at an experimental stage. This review attempts to present thecurrent status of these add-on/combination approaches with particular focus on the medicinal chemistry aspects.

Keywords: Serotonin, norepinephrine, dopamine, SERT, DAT, NET, SSRI, 5-HT1A, 5-HT2C, 5-HT2A, reuptake inhibition,combination, add-on, augmentation, ASRI.

INTRODUCTION

Drug therapies for treatment of depression disorders havebeen available since the late fifties, where the first tricyclicantidepressants (TCAs) and monoamine oxidase inhibitors(MAOI) became available. Amitriptyline (1) was one of themost prominent members of the TCA class and among thecore pharmacological activities accounting for their antidep-ressant effect were potent serotonin transporter (SERT)inhibition and norepinephrine transporter (NET) inhibition.However, this drug class was also associated with severeside effects, eg dry mouth (see ref [1] for further references).

In the late sixties and early seventies, the importance ofSERT in the regulation of mood became more obvious. Thisresulted in the formulation of the monoamine hypothesis ofdepression [2] and the first selective SERT inhibitors (theSSRIs), that were discovered, were zimelidine (2) [3] andfluoxetine (3) [4]. In the following years, a large number ofstructures claiming SSRI activity were patented.

The advent of the SSRIs meant a major breakthrough inthe treatment of depressive illnesses. Not so much in termsof better efficacy, but more in terms of a highly improvedside effect profile, which allowed a much larger patientpopulation to be treated. Particularly the improved overdosesafety of the SSRIs was a major improvement. During theeighties and nineties, a number of SSRIs came on the marketand with them the shortcomings of these drugs also becameclear: full antidepressant effect requires 3-6 weeks oftreatment, and a significant number of the patients (30%) do

*Address correspondence to this author at the Medicinal ChemistryResearch, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby-Copenhagen,Denmark; E-mail: [email protected]

not respond to treatment [5]. Apart from that, a number ofother side effects, such as sleep and sexual disturbances, alsobecame apparent.

During the past ten years, the demand from society forbetter treatments of depression has increased substantially.Where success of treatment earlier was equated to reductionin symptoms as measured by various rating scales (e.g. 50%reduction on the HAM-D scale), it is now being replaced bydemand for full remission and patient wellness. Combinedwith the fact that today the total potential patient populationis considered much larger than earlier anticipated, a renewedand intense research interest was triggered within thedepression field in general.

A number of drug targets have been pursued, includingother monoamine and non-monoamine receptors and trans-porters, various peptide receptors, hormone receptors, enzy-mes, and the immune system (see eg refs [6] and [7]). Lately,the importance of neuroplasticity has also become subject ofinvestigation [8]. However, with the exception of theserotonin noradrenaline reuptake inhibi-tors (SNRIs), noneof these approaches have so far resulted in therapies that arejust as efficacious as the SSRIs. The future will showwhether some of them will be successful.

Driven by the success of the SSRIs, it has been a popularstrategy to pursue various augmentation princi-ples toserotonin (5-HT) reuptake inhibition, thereby hoping toimprove on some of the shortcomings of the SSRIs. Fastonset of action, in particular, has been in focus [9]. Thisreview will mainly focus on the medicinal chemistry aspectsof these SRI augmentation strategies. For other aspectsregarding SRIs, including more biological andpharmacological related information, the reader is referred to

1802 Current Topics in Medicinal Chemistry, 2006, Vol. 6, No. 17 Moltzen and Bang-Andersen

a number of excellent reviews published in recent years [1,6, 7, 10, 11].

SELECTIVE SEROTONIN REUPTAKE INHIBITORS(SSRIs)

Since the early seventies and until today, a large numberof SSRIs have been described and marketed. However, morethan 95% of the SSRI market is covered by 5 products:Fluoxetine (Lilly: ProzacTM) 3, Escitalopram (Lundbeck/Forrest Labs: LexaproTM, CipralexTM) 4, Sertraline (Pfizer:ZoloftTM) 5, Paroxetine (GSK: PaxilTM) 6, and Fluvoxamine(Solvay: FevarinTM) 7. A few new SSRIs are still beingdeveloped. However, they cannot be considered of impor-tance for two main reasons: the currently marketed SSRIsare all as efficacious as one can expect from this class ofdrugs and most of them will go generic within a few years,thus making it very difficult for new me-too SSRIs to makeit to the market. As will be outlined below, Escitalopramconstitutes a special case. It was originally marketed as theracemate, but recent evidence has shown that the R-enantiomer inhibits the action of the S-enantiomer, thusmaking the now marketed pure S-enantiomer a much moreefficacious antidepressant with allosteric action on SERT.

As mentioned above, this class of drugs provided a majorimprovement compared to treatments with TCAs andMAOIs. Although the SSRIs cannot be considered more

efficacious in severe depression than the TCAs [12], theirmuch improved side effect profile warrants their widespreaduse. The main problems encountered with SSRIs areCYP450 liver enzyme interactions, slow onset of action,poor or no effect in at least 30% of the patients, sexual dys-function, insomnia, and nausea. Some withdrawal symptomshave also been observed. However, these side effects aremuch more benign than the severe anticholinergic andcardiovascular problems seen with TCAs [1].

This benign profile has allowed the SSRIs to be exploredin a much wider range of indications, and clinical efficacyhas now also been demonstrated in panic disorder, generalanxiety disorders, post traumatic stress disorder, socialphobia, obsessive-compulsive disorder, eating disorders, pre-menstrual dysphoric disorder, and a further range ofindications are still being explored [1].

ALLOSTERIC SITE ON THE SEROTONIN TRANS-PORTER

The pharmacological selectivity of marketed SSRIs isrelative rather than absolute, and these agents can haveclinically significant properties that differentiates one drug inthis class from another [13, 14]. It must also be emphasizedthat Fluoxetine and Citalopram were first marketed as race-mates, whereas Paroxetine and Sertraline were introduced assingle enantiomers [15], and that single enantiomers of both

Scheme (1). Amitriptyline and Selective Serotonin Reuptake Inhibitors (SSRIs).

N

Amitriptyline (1)

N

N

Br

Zimelidine (2)

OHN

F3C

Fluoxetine (3)

NO

NC

F

S-Citalopram (4)

NH

Cl

Cl

Sertraline (5)

O

OOHN

F

Paroxetine (6)

O NO

NH2

CF3

Fluvoxamine (7)

N

NH

N

NH2Cl

Cl

NH

O

O

SoRI-6238 (8)

Serotonin Reuptake Inhibitors Current Topics in Medicinal Chemistry, 2006, Vol. 6, No. 17 1803

Citalopram and Fluoxetine have been pursued as second-generation SSRIs [14]. In the case of Fluoxetine, theenantiomers are equipotent as SRIs, but the R-enantiomer isan antagonist at human 5-HT2A and 5-HT2C receptors leavingthe S-enantiomer as the more selective SSRI [16]. However,due to cardiovascular side effects, R-Fluoxetine never madeit to market. In the case of Citalopram, it has been shownthat the SRI activity is attributable to the S-enantiomer [17,18], Escitalopram. The R-enantiomer is about a factor of 30-40 times less potent than Escitalopram at the humantransporter [19, 20]. In 2002, Escitalopram was launced as anew single-enantiomer drug (Lundbeck/Forrest Labs:LexaproTM, CipralexTM).

Today, Escitalopram has demonstrated improved clinicalefficacy as antidepressant when compared to SSRIs and withdemonstrated efficacy in anxiety disorders [21, 22]. Theimproved effect was first demonstrated in a human clinicalstudy in patients with major depressive disorder, and in non-clinical studies using rat behavioural models of depression.In both clinical and preclinical studies it was found that theonset of effect of Escitalopram versus placebo was fasterthan Citalopram versus placebo [23]. This was a surprisingresult at that time because the animals and patients in thesetwo studies received equivalent amounts of the S-enan-tiomer. However, the Citalopram-treated groups alsoreceived R-Citalopram. Since then it has been shown in anumber of studies that the R-enantiomer in Citalopram actu-ally counteracts the activity of the S-enantiomer in in vitroand in vivo mechanistic models [24-27] and in behaviouralanimal models [19, 23, 28-30]. For a more detaileddiscussion regarding Escitalopram and the surprising role ofthe R-enantiomer of Citalopram, the reader is referred to anumber of reviews published recently [15, 22, 31].

The mechanism behind the inhibitory action of R-Citalo-pram on Escitalopram may be related to its action on theallosteric binding site on SERT [32]. The existence of anallosteric binding site on SERT and its possible relevance forthe effect of antidepressants has been known since the early1990s [33]. In vitro binding kinetics using brain neuronalmembranes and platelet membranes demonstrated theexistence of this secondary, affinity-modulating binding siteon SERT. It is a low-affinity binding site and only Escitalo-pram and to a lesser extent Paroxetine exert an allostericeffect via this mechanism, which is not correlated to theiraffinity for the primary high-affinity binding site and theirSRI potencies. Interestingly, SoRI-6238 (8) has been descri-bed as an allosteric modulator without affinity for theprimary binding site [34].

Recently, the allosteric binding site has attracted renewedinterested in connection with the improved antidepressanteffect seen for Escitalopram, and it has been shown thatEscitalopram and R-Citalopram via this site can modulate theassociation [35] and dissociation [36, 37] rates of Escitalo-pram from the primary binding site. Furthermore, it has beenshown that Escitalopram stabilises the binding of [3H]-Escitalopram to hSERT, but not the binding of other SSRIs[37]. In comparison, Paroxetine also stabilises its ownbinding, but to a lesser extent, and it has no effect on thebinding of the other ligands. R-Citalopram is about a factorof 3 times less potent than Escitalopram suggesting some

degree of stereoselectivity at the allosteric site [37]. Thus,Escitalopram may be superior toward SSRIs because of itsunique interaction with the allosteric binding site on SERT,making this site especially interesting as a future target forthe design of improved antidepressants. The term ASRI(Allosteric Serotonin Reuptake Inhibitors) [38] has beenassigned to these new types of dual acting compounds.

In order to assist the design of novel SSRIs and to under-stand the structural organisation as well as the molecularmechanisms responsible for the function of SERT, a numberof homology models have been developed during the yearsbased on non-crystallographic approaches [39], but alsobased on X-ray structures of related transporters, such as theEscherichia coli Na+/H+ antiporter [40] and the lactosepermease symporter (lac permease) [41].

Recently, an X-ray structure of a bacterial homologue ofSERT from Aquifex aeolicus was published [42]. As thistransporter belongs to the same family as SERT, thisstructure may offer an opportunity to build a more reliablecomputational model of SERT than hitherto possible. Apreliminary insight into such a model and its limitations hasrecently been described [43], but it is probably only a matterof time before a more comprehensive account will be pub-lished. It may be envisaged that such a model will give betterinsight into the primary binding site of SERT, but hopefullyalso into the allosteric binding site, which has been shown tobe independent of the primary binding site [36, 44] andlocated at the C-terminal part of SERT containing thetransmembrane domains 10 to 12 [45].

AUGMENTATION STRATEGIES

The concept of combining serotonin reuptake inhibitionwith other pharmacological activities within treatment ofdepression has attracted much research attention during thepast 15 years. Two different approaches have mainly beenattempted: either combination of an SSRI with othersubstances of varying pharmacological activity (add-on) orpreparation of molecules with build-in activities at multipletargets. Although the terms combination and augmentationare sometimes used interchangeably [46], some distinctioncan be made. Thus, for add-on treatment the term combi-nation refers to the use of more than one disease-specifictreatment to treat a specific disease, ie pharmacotherapy oftreatment-resistant depression by the use of at least twodifferent antidepressants, whereas augmentation refers to theaddition of a non-antidepressant medication, ie addition oflithium or an antipsychotic to an SSRI. In the case of singlemolecules with build-in activities at multiple targets, theaugmentation term will be used to describe both the additionof targets known to treat related symptoms, eg 5-HT1Aagonism to treat anxiolytic symptoms, but also to describeimprovement of the antidepressant potential, eg 5-HT1Aantagonism to increase onset of antidepressant action.

The discovery by Artigas of the augmentative effect of 5-HT1A antagonists on the antidepressant efficacy of SSRIs[47] triggered the development of these combination/augmentation strategies. The main focus was and still is -to obtain faster onset of action, which is one of the majorproblems in depression, but other unmet needs have alsobeen addressed, for example treatment resistance and sleep

Current Topics in Medicinal Chemistry, 2006, Vol. 6, No. 17 Moltzen and Bang-Andersen

disturbances. In more recent years, a broader range ofindications has been targeted, eg treatment of bipolardisorder with a combination of SSRIs and antipsychotics.

In the following, a survey of the various medicinalchemistry strategies reported in the literature on this subjectduring the last 15 years will be presented.

SERT/NET and SERT/NET/DAT Inhibitors

The SERT/NET uptake inhibitor class is relatively newand so far there are only three on the market for depression(Scheme 2): Venlafaxine, 9, Duloxetine (CymbaltaTM), 10,and Milnacipran, 11. NET inhibition is a component of theprofiles of the old TCAs, and the antidepressant effect ofelevating the norepinephrine (NE) levels in the brain haslong been realized [48]. The NET effect is mainly associatedwith improvement of anhedonic and melancholic features ofdepression as well as higher remission rates [49, 50]. Theantidepressant effect of selective NET uptake inhibition issupported by the NET-selective Reboxetine, 13, which is onthe market and displays clinical efficacy, particularly inmajor depression [50].

Venlafaxine has been on the market since 1994 and is atrelatively high doses (>225 mg) associated with faster onsetof action than some of the SSRIs [52]. Duloxetine is a potentSERT/NET inhibitor and has recently entered the marketwhere it has been positioned as an antidepressant, possiblywith pain relieving properties [53, 54]. Milnacipran is asomewhat weaker SERT/NET inhibitor, but still shows clini-cal efficacy [51]. Sibutramine, 12, is also a selective SERT/NET inhibitor, but has been marketed for treatment ofobesity [55].

The major issue with this type of profile concerns safety.Although the new generation is devoid of the anticholinergicand antihistaminic activity of the old TCAs, the increasedNE tone still represents an increased risk of side effects,primarily blood pressure changes. This is also seen inclinical studies [52, 56], and for new derivatives of this kindthe challenge is to find the right balance between increasedefficacy, putatively greater response and remission rates and,on the other side, norepinephrine-related side effects.Duloxetine might be the first compound of this type on themarket with relatively modest effect on heart rate and bloodpressure.

The success of SERT/NET inhibitors has initiated anincreased activity to find new derivatives. The Lilly grouphas published further SAR efforts around Duloxetine [54]resulting in two related structures showing potent SERT/NET inhibition: 14 (SERT: Ki 0.5 nM, NET: Ki 4.4 nM) [57]and 15 (SERT: Ki 1.4 nM, NET: Ki 3.1 nM) [58].

In an older work, Servier presented S33005, 16, whichdisplays potent SERT uptake inhibition (Ki 2.1 nM) andmore modest NET inhibition (Ki 1514 nM). However, thecompound is effective in increasing 5-HT and NE levels inrat frontal cortex (500% for both 5-HT and NE at 10 mg/kg)as measured by microdialysis [59].

Recently, triple compounds with uptake inhibiting acti-vity at SERT, NET, and the dopamine transporter (DAT)have started to appear. The most prominent example isDOV-21947, 17, which has been reported to be in clinical

trials [60]. The interesting challenge for these compoundswill be whether the DAT component is tolerable without in-ducing abuse liability due to increased dopamine stimulation.

In the patent literature, the interest in this area is alsoreflected by the increasing number of patents beingpublished, both on dual and triple active compounds. Someof the more recent ones are listed in Table (1).

SERT Inhibitors/5-HT1A Antagonists

During the early nineties, it was discovered that blockadeof 5-HT1A autoreceptors in raph nuclei augments theserotonergic output in cortical and other brain areas follo-wing application of SRIs as shown by both microdialysis andelectrophysiological studies [61]. The importance of thisdiscovery was emphasised by Artigas clinical studycombining Paroxetine with Pindolol (18) [47], which besidesbeing a beta blocker is also a 5-HT1A antagonist. A rapidimprovement of the depressive symptoms in the participatingpatients was observed. This finding was rationalised by thehypothesis that the 4-6 weeks of treatment with SRIsnormally required to obtain full antidepressant efficacy leadsto desensitisation of 5-HT1A autoreceptors, thus allowing theserotonergic neurons to resume their normal function. Simul-taneous application of a 5-HT1A antagonist inhibits thisfeedback mechanism. This would in turn allow an immediateand sufficient increase in extracellular concentrations of 5-HT to obtain antidepressant efficacy.

It is still being discussed whether this hypothesis holds[62]. A number of similar clinical trials have been performed,and the results are very mixed, although a recent meta-analysis concludes that Pindolol seems to hasten theresponse to SSRIs in depression [63]. It has also beenquestioned whether the applied 7.5 mg dose of Pindololwould be sufficient to occupy the 5-HT1A receptors, but PETstudies have now confirmed that this is indeed the case [64].It has also been suggested that stimulation of postsynaptic 5-HT1A receptors is important for antidepressant action, and 5-HT1A antagonism would be detrimental to this effect. Thisissue is still not fully resolved. Finally, it should bementioned that genetic links between depression and SERTand 5-HT1A receptors have recently been reviewed [65].

A large number of groups have been pursuing theSERT/5-HT1A concept. Combinations of SSRIs with various5-HT1A antagonists have appeared in the patent literature.This includes combinations with Pindolol and other betablockers [66-69], with the silent 5-HT1A antagonist WAY-100635 (19) [70], and with other types of 5-HT1 antagonists[71-75]. However, none of these approaches have so farreached the market.

The concept of combining the two effects in onemolecule has attracted much more attention. The Eli Lillygroup has recently published a series of papers on Pindololderivatives where the isopropylamino group has been repla-ced by a 5-HT1A active biarylalkylamino moiety exemplifiedby 20 [76-79]. A comprehensive SAR study shows that invitro the series potently binds to 5-HT1A receptors and toSERT. The series is in general antagonistic at 5-HT1Areceptors according to testing in a [35S]GTPgS assay in cellstransfected with human 5-HT1A receptors. Compound 20 (5-


Scheme (2). Combined SERT/NET and SERT/NET/DAT inhibitors.

Table 1. Recently Patented SERT/NET and SERT/NET/DAT Inhibitors

Structure Comment Reference

SERT, NET, DAT reuptake inhibitors.

Lundbeck, 2006[147]

SERT, NET reuptake inhibitors.

Baxter et al, 2006[148]

S

N

HN

HN

N

OBr

N

OH

O

O

NH

S

H2N

N

O

NCl

NH

O

O

O

H

NH

O

S

S

N

NH

CF3

HO

N

O

NH

Cl

Cl

Venlafaxine (9) Duloxetine (10) Milnacipran (11)

Sibutramin (12) Reboxetine (13) (14)

(15) S33005 (16) DOV-21947 (17)


(Table 1) Contd.


SERT (Ki 27 nM), NET (Ki 62 nM)uptake inhibitor.

Pfizer, 2005

[149]


Lilly, 2004[150]


Lilly, 2005[151]

SERT, NET

reuptake inhibitors.

Lilly, 2004

[152]

SERT (


(Table 1) Contd.



Dupont, 2001[155]


BMS, 2006[156]

HT1A: Ki 14 nM, SERT: Ki 0.86 nM) was selected based on apotent effect in microdialysis with 700% increase in 5-HTconcentration as measured in rat hypothalamus at 10 mg/kg,po. The effects on SERT and 5-HT1A receptors of 20 werealso substantiated in vivo [80].

The Lilly group has also reported on structures relating tothe selective 5-HT1A antagonist WAY100635 [81-85]. Datawere presented on LY433221, 21 [86-89], and they showedpotent affinity for cloned human 5-HT1A receptors (Ki 5.4nM), inhibition of synaptosomal [3H]5-HT uptake (IC50 0.8nM), and inhibition of 5-HT-stimulated [35S]GTP- g S binding(Ki 2.7 nM, Emin 12.4%). The compound also displaysaffinity for 5-HT2A receptors (Ki 13.1 nM). A large numberof in vivo studies were reported, indicating antidepressantand anxiolytic potential, eg the compound increased extra-cellular 5-HT by 600% in prefrontal cortex (30 mg/kg, po).

Combination of the Pindolol/SSRI motives has also beenaddressed by the GSK group. Based on a functional highthroughput screening using a [35S]GTP- g S binding assayfollowed by optimisation resulted in compound 22 [90]. TheSAR study included variations of the indole moiety and thelinker, whereas the benzoxazinone part was kept. As in othersimilar SAR studies, the main issue was to maintain highaffinity for and antagonism/low partial agonism at 5-HT1Areceptors and potent SERT inhibition. This wasaccomplished in 22 (5-HT1A: Ki 0.3 nM (intrinsic activity0.2), inhibition of synaptosomal [3H]5-HT uptake Ki 6.3nM). The compound also showed affinity for 5-HT1B (pKi8.1) and 5-HT1D (pKi 8.7) receptors, but was otherwiseselective. Oral bioavailability and brain penetration couldalso be demonstrated.

The Wyeth group has published a series of studiestowards compounds combining SERT-active with 5-HT1A-active moieties, respectively [91-96]. For the SERT-activepart the main focus is on the 3-indolyl-alkylamino scaffold(known from eg the potent SERT inhibitor indalpine),

whereas the 5-HT1A part mainly circles around an aryloxy-alkyl motif. Some representative examples are shown inScheme 3, structures 23 and 24. The profiles of these twoderivatives demonstrate the main challenges in this work.Derivative 23 is rather weak at both SERT and 5-HT1A([3H]5-HT uptake: Ki 45 nM, 5-HT1A: Ki 78 nM) and is apartial 5-HT1A agonist according to [

35S]GTP- g S assaytesting. Derivative 24 is more potent ([3H]5-HT uptake: Ki4.5 nM, 5-HT1A: Ki 10.7 nM) and shows no 5-HT1A agonism.However, both 23 and 24 bind potently to a 1 adrenoceptors(Ki 4.7 nM and 4.6 nM, respectively). Extensive SARvariations on both the aryloxy group as well as the linkerwere performed, whereas some substituent variations on theindole moiety were performed. However, the optimal profilewas not reached. This optimisation challenge: to obtainpotent SERT inhibition and 5-HT1A antagonism withoutaffecting other monoamine receptors is a general problemwithin this field.

The Lundbeck group faced similar challenges. Anapproach similar to the Wyeths was used combining the 3-indolylalkylamine moiety as the SERT-active part and theortho-alkyloxyarylpiperazine as the 5-HT1A part [97]. Themain result of this work was Lu 36-274, 25, which showspotent SERT inhibition ([3H]5-HT uptake: Ki 5 nM) and 5-HT1A antagonism (Ki 4.5 nM, no partiality). Selectivitytowards a 1 adrenoceptors and D2 receptors was a mainproblem, but it was solved by introducing the 8-cyano groupin the benzodioxane ring. Another problem was to obtain 5-HT1A antagonism with no partiality. This was solved byintroducing the 6-chloro substituent in the indole ring. Lu36-274 shows a 500% increase in extracellular 5-HTconcentration in rat frontal cortex (16 mg/kg, sc), and itshows a potent and immediate effect in the schedule-inducedpolydipsia model, which is an indicator of antidepressantefficacy [98].

Although the main focus has been on 5-HT1A antagonists,there has also been some interest in developing 5-HT1A

N

N

S


agonists. Clinically, combination of Buspirone (BusparTM, a5-HT1A partial agonist) with various SSRIs has beenattempted and in a smaller study including thirty outpatientsimproved response- and remission rates were observed [99].However, these results have not been substantiated in largertrials, and compounds with this level of 5-HT1A efficacymight not be the optimal profile for combination withserotonin reuptake inhibition. It shall be mentioned thatanecdotal reports indicate that co-prescriptions of Buspironeand SSRIs occur to some extent.

VN2222, 26, is the result of an optimisation startingmainly from known selective 5-HT1A agonists and, some-what unexpectedly, building in SERT inhibition via abenzothiophene moiety [100-102]. As expected by a 5-HT1Aagonist, VN2222 acutely reduces extracellular 5-HT levels inrat striatum, but after 14 days of chronic treatment 5-HTlevels are unaffected by VN2222, indicating desensitizationof the 5-HT1A autoreceptors [103]. Effect in the learnedhelplessness test was demonstrated [104].

The indole derivative Vilazodone (EMD68843), 27, is avery interesting compound. It was developed by MerckKGaA via systematic structural modification of indole-alkylphenyl piperazines [105] and is now being developedby Genaissance Pharmaceuticals. It recently entered phaseIII clinical trials. Vilazodone is a potent SERT inhibitor([3H]5-HT uptake: IC50 0.5 nM), a 5-HT1A ligand (IC50 0.2nM) and an agonist at 5-HT1A as measured in the [

35S]GTP-g S assay. However, in vivo the compound behaves as a 5-HT1A antagonist and induces a 2- to 3- fold increase in extra-cellular 5-HT concentration in rat frontal cortex [106]. Thisdiscrepancy is apparently still not understood. The Merckgroup has further elaborated on the SAR around Vilazodoneresulting in eg 28 (5-HT1A: IC50 2.5 nM (agonist), [

3H]5-HTuptake: IC50 0.2 nM), which increased 5-HT concentration 2-to 3- fold in rat frontal cortex [107].

Besides the SERT/5-HT1A active compounds describedso far, a rather large number of further structures with similarprofiles have been claimed in the patent literature. Since nofurther biological data are available, only representativestructures and references are given in Table (2).

SERT Inhibition/Antipsychotics and SERT Inhibition/Mirtazepine or Mianserin

Antipsychotics show only modest efficacy as mono-therapy of depression, but they are effective in those patientswho also present psychotic symptoms [46]. However, anincreasing body of evidence suggests that antipsychoticsmay also augment the antidepressant action of SSRIs in non-psychotic patients and be useful in the treatment of treat-ment-resistant depression [108] and bipolar disorder [109].

Augmentation with typical antipsychotics has never beenwidely used because of the risk of extrapyramidal symptoms(EPS) and/or tardive dyskinesia [110]. The introductionduring the 1990s of the atypical antipsychotic drugs, whichdo not induce EPS to the same extent, spurred the interest forcombining SSRIs with an atypical antipsychotics in order topotentially augment the effects of SSRIs.

In the meantime, a growing number of clinical trials havebeen published on the combination of SRIs, in particular

SSRIs, with atypical antipsychotics. Thus, Risperidone, 29[111, 112], Olanzapine, 30 [113-115] Ziprasidone, 31 [116]Aripiprazole, 32 [117, 118] and Quetiapine, 33 [119] haveall shown superior efficacy in the treatment of treatment-resistant depression as add-on to various SSRIs. Further-more, Quetiapine in combination with ongoing SRI therapyhas been shown to be effective in treatment of treatment-refractory obsessive compulsory disorder [120] and in thetreatment of co-morbid anxiety in depressed patients [121].Olanzapine in combination with Fluoxetine (SymbiaxTM) hasreached the US market for the treatment of bipolardepression [122], whereas Risperidone in combination withParoxetine only showed modest effects when added to amood stabilizer in bipolar depression [123]. Thus, combiningan SSRI with an atypical antipsychotic drug cannot be seenas a common class of drugs that gives similar effects. Thismay not be too surprising, as the atypical antipsychotics alldisplay slightly different multireceptorial pharmacologiesthat probably account for these differences. The success ofsuch a combination will furthermore depend on compound-specific limitations known for all of the atypical antipsy-chotics, such as varying degrees of potential for inducingweight gain/metabolic disturbances, QTc prolongation, andelevation of prolactin [124].

Mirtazepine (and Mianserin) is a potent antagonist atcentral a 2-adrenergic auto- and heteroreceptors, and anantagonist at 5-HT2 and 5-HT3 receptors [125]. It has beenshown that Mirtazepine is an effective antidepressant in itsown right [126], but beneficial effects in combination withSSRIs have also been demonstrated [127].

The mechanism behind these combinations has not beenfully elucidated, and different groups have put forwardvarious explanations [119, 128]. It has been suggested thatblockade of 5-HT2A receptors is of importance because a lowdose of Risperidone supposed to block only 5-HT2Areceptors are indeed effective as add-on [129]. It has beensuggested, that the ability of antipsychotics to augment thetherapeutic efficacy of SSRIs in major depression andtreatment-resistant depression may be due, at least in part, topotentiation of SSRI-induced increases in cortical dopamineand norepinephrine levels [130, 131].

SERT Inhibition/5-HT2A Antagonism

Multiple lines of evidence are consistent with thehypothesis that blockade of 5-HT2A receptors might enhancethe therapeutic effectiveness of SSRIs [128, 129, 132]. It hasalso been hypothesized that blockade of 5-HT2A receptorsmight reduce some of the side-effects related to SSRItreatment, eg sexual and sleep disturbances [133], making acombined SERT inhibitor/5-HT2A antagonist an attractivetarget for an improved antidepressant.

Trazodone (DesyrelTM) 34 and Nefazodone (SerzoneTM)35 are antidepressants, which both show high affinity for 5-HT2A receptors (34: Ki 11 nM and 35: Ki 32 nM) andsomewhat lower affinity for SERT (34: Ki 115 nM and 35:Ki 181 nM) as measured in rat cortex homogenate [133,134]. It has been shown in vivo in rat and mouse brain, thatNefazodone is an antagonist at 5-HT2A receptors. The in vivoSERT activity has been more difficult to verify in variouslaboratories [133-135], and this may be due to the relativelyweak in vitro affinity for SERT. It has also been shown that


Scheme (3). Combined SERT inhibitors and 5-HT1A antagonists.

Table 2. Combined SERT Inhibitors and 5-HT1A Antagonists Reported in the Patent Literature


5-HT1A modulator and SERT inhibitor.

Sumitomo Pharmaceuticals

2003

[157]

5-HT1A antagonist and SERT inhibitor.

Welfide Corp.

2000

[158]

HN O NH

OH NN

N

O

O

N

N O

S

O OH

NH

N

S

O

N

ON

N O

HN

O

ArO

N

NH

R

O O

N NH

Cl

N

HN

N

O

O

CN

Cl N

S

OH

N

O

N

HN

N

O

NH2

O

NC

N

HN

N

NC

O

O

HN O

Pindolol (18) WAY-100635 (19) (20)

LY433221 (21) (22)(23): R = H, Ar =

(24): R = F, Ar =

Lu 36-274 (25) VN2222 (26)

Vilazodone (27) (28)

HN

NBr

Cl

N O

Cl

Cl OH O

O

NN


(Table 2) Contd.



Pierre Fabre

1998

[159]

5-HT1A ligand and SERT inhibitor.

American Home Products

2000

[160]



2000

[161]



2000

[162]



2000

[163]



2000

[164]



1999

[165]

HN O

OH

NHO

F3C

NH

ON

NH

FO

N N

NH

F

O

HNN N

NH

CN

HNN

CN

S

O

O

N

NH

NH

F

ONH

NH

F

O

O


(Table 2) Contd.




1999

[166]



1999

[167]



1999

[168]

5-HT1A/1B/1D antagonist and SERTinhibitor.

BASF

1999

[169]

5-HT1A/1B/1D antagonist and SERTinhibitor.

BASF

1999

[170]


GSK

2006

[171]

NH

ONH

NH

F

ONH

NH

F

N

NH

ONH

NH

F

HN

N N

N

N

N

O

O

N N

N

S

O O

O

N

N

O

N

O

N

N

N


(Table 2) Contd.


5-HT1A ligand and

SERT inhibitor.

Adir et Co

2001

[172]

Scheme (4). Atypical antipsychotics.

Nefazodone occupies 5-HT2A receptors in humans at startingclinical doses [136]. Trazodone and Nefazodone also displayaffinity for a number of other receptors believed to berelevant at therapeutic doses, most notably 5-HT1A (partialagonist) and a 1 for Trazodone [133, 137], and NET and a 1for Nefazodone [133]. Yamanouchi was developing a dualacting SERT/5-HT2A compound, Lubazodone (YM-992/YM-35995) 36, which is a more potent SERT inhibitor thanTrazolone and Nefazodone. Lubazodone is also a morebalanced SERT/5-HT2A compound (SERT: Ki 21 nM, 5-HT2A: K i 86 nM) [138] displaying good selectivity toward arange of monoaminergic receptors of which the closestaffinity was found for a 1 adrenoceptors (Ki 200 nM) and 5-HT2C receptors (K i 680 nM) [138]. Lubazodone has been inphase II clinical trials, but the development was discontinuedin 2001 due to erosion of the SSRI market in the US. TheLilly group has also reported on structures that are evenmore balanced with regard to SERT versus 5-HT2A.

LY367265, 37, has been shown to have high affinity forSERT (Ki 2.3 nM) and 5-HT2A receptors (Ki 0.81 nM), and ithas been shown to be a potent inhibitor of [3H]5-HT uptakeinto rat synaptosomes (IC50 3.1 nM) with selectivity towardsNET (IC50 > 1000 nM) [139]. This compound is no longerunder development [10]. Lilly has described a number offurther analogues of LY367265 in the patent literature, andalso Pfizer, Lundbeck, Merck KGaA, and Baylor Universityhave filed patents claiming combined SERT inhibitors and 5-HT2A antagonists. Representative structures and referencesfor these patents are given in Table (3).

SERT Inhibition/5-HT2C Antagonism

Selective 5-HT2C antagonists have mostly received inte-rest as potential anxiolytics, but also as potential antidep-ressants, whereas 5-HT2C agonists have been related to anti-depressant activity [140-145]. Furthermore, it was recentlydemonstrated that blockade of 5-HT2C receptors potentiates

N

N

O

HN

N

S

N

N

S

N

N

N

O

HO

N

N

N

S

NH

O

Cl

N

N

O

N

N

F

O

N

N

Cl

Cl

OHN O

Olanzapine (30) Ziprasidone (31)

Quetiapine (33)

Risperidone (29)

Aripiprazole (32)


Scheme (5). Combined SERT inhibitors and 5-HT2A/5-HT2C antagonists.

Table 3. Combined SERT Inhibitors and 5-HT2A Antagonists Reported in the Patent Literature



Baylor University, 2005[173]

Novel composition comprising an SSRI, particularly Sertraline, and a selective inhibitor for the binding of serotonin at the 5-HT2A site for the treatment of depression and anxiety disorders

Pfizer, 2005

[174]


Pfizer, 2002[175]


Pfizer, 2001[176]

N

N

Cl

N

NN

O

N

N

Cl

N

NN

O

O

NH

OO

F

NH

N

F

N

N S

O

O N

NN

N

N

O

N

Lubazodone (36)

Trazodone (34) Nefazodone (35)

LY-367265 (37) (38)

N

N

Cl

O

F

N

N

Cl

N

NH

O

O

Cl

N

Cl

N

NH

O

O


(Table 3) Contd.



Lilly, 1999[177]


Lilly, 1999[178, 179]


Merck KGaA, 1998[180]


Lundbeck, 1995[181]

both the neurochemical and antidepressant-like behaviouralaction of SSRIs [146]. In in vivo microdialysis the 5-HT2Cselective antagonists SB-242084 and RS-102221 substan-tially augmented the serotonergic response to Citalopram, asindicated by a 900% increase in extracellular 5-HT levels ascompared to baseline values. The two selective 5-HT2Cantagonists did not alter the 5-HT level when given alone,and Citalopram gave an increase of approximately 400-500%relative to baseline [146]. Thus, several lines of evidence

support the combination of an SSRI with a 5-HT2Cantagonist in order to find an improved antidepressant.

Compounds with this specific profile have been reportedin a number of patent applications, but not specifically in theliterature. However, some of the compounds discussed abovetargeting SERT/5-HT2A will probably also exert 5-HT2Caffinity, as the SAR for 5-HT2A and 5-HT2C often follows asimilar pattern in chemical series. R-Fluoxetine may to some

NH

N

F

N

O

NH

N

NSO

O

F

NH

N O

N

Cl

O

NH

N

HN O

Cl


extent be representative for such a compound (SERT: Ki 7.7nM and 5-HT2C: Ki 68 nM), although the increase inextracellular 5-HT as measured by in vivo microdialysis,when compared to the SSRI S-Fluoxetine, does not matchthe combinations described above [16]. The 5-HT2C antago-nism of R-Fluoxetine is probably too weak.

The Adir group has filed a patent in year 2000 onSERT/5-HT2C compounds and described in vitro data for arepresentative compound from this application, 38.230

Compound 38 exhibited a Ki value of 9.8 nM for SERT asmeasured by displacement of [3H]Paroxetine and an affinitybetween 1 and 10 nM for 5-HT2C receptors as measured bydisplacement of [3H]mesulergine. Since no biological dataare available for specific compounds in the other patents,representative structures and references for these are given inTable (4).

SERT Inhibitors/Other

A number of other SRI combinations have been descri-bed. While some degree of validation exists for a few ofthese possibilities, like combinations with 5-HT1B/1D and a 2

antagonists, respectively, most of these new suggestionshave only appeared in the patent literature so far. This is forexample the case with combinations with GABA-A/GABA-B ligands. The future will show whether these approachesare viable. A summary is shown in Table (5).

CONCLUSIONS

Serotonin reuptake inhibition has meant a major break-through in the treatment of depression over the last 50 years.The drugs have been refined over the years, and with theadvent of the SSRIs it seems that this type of treatment isclose to have reached its full potential as stand-alonetreatment. Due to the relatively benign side effect profiles ofthe SSRIs, their use has spread out to a number of differentmood and anxiety disorders, and further uses will undoub-tedly be found. However, SSRI treatment does not constitutethe ideal depression treatment. The issues with slow onset ofaction, treatment resistance in almost 30% of the patients,and various other side effects as mentioned above cannot beaddressed by SSRIs alone.

Table 4. Combined SERT Inhibitors and 5-HT2C Antagonists Reported in the Patent Literature


5-HT2C antagonist and SERT inhibitor.

Lundbeck, 2004[182]


Lundbeck, 2004[183]


Lundbeck, 2003[184]

Use of compounds and composition of compounds having SRI activity and 5-HT2C antagonistic, partial agonistic or inverse agonisticactivity for the treatment of depression and other affective disorders

Lundbeck, 2001

[185]

Use of combination of Irindalone and SRIs or any other compounds, which causes elevation in the level of 5-HT, for the treatment ofdepression and other affective disorders

Lundbeck, 2001

[186]

S

HN

F

S

HN

Cl CF3

S

N

HN

CF3


Table 5. Other SRI Combinations

Combination for treatment of depression Reference

Concurrent administration of an SRI, 5-HT, a peripheral decarboxylase inhibitor or tetrahydrobiopterin Duke University, 2005 [187]

Administration of a 5-HT3 antagonist with an SRI Lundbeck, 2005 [188]

Administration of a 5-HT3 antagonist with an SRI Pfizer, 2002 [189]

Administration of a 5-HT3 antagonist with an SRI Eli Lilly, 1999 [190]

Compounds with combined SRI activity and 5-HT1D antagonism Eli Lilly, 2004 [191]

Compounds with combined SRI activity and 5-HT1B/D antagonism Merck KgaA, 2000 [192]

Compounds with combined SRI activity and 5-HT1B antagonism or partial agonism Astra, 1999 [71]

Concurrent administration of an SRI and a 2 antagonist yohimbine Yale University, 2004 [193]

Compounds with combined SRI activity and a 2 antagonism Abbott, 1997 [194]

Compounds with combined SRI activity and NK1 BMS, 2006 [195]

Compounds with combined SRI activity and NK1 BMS, 2006 [196]

Compounds with combined SRI activity and NK1 Glaxo, 2005 [197]

Compounds with combined SRI activity and NK1 AstraZeneca, 2005 [198]





Compounds with combined SRI activity and NK1 Glaxo, 2004 [203]

Compounds with combined SRI activity and NK1 UCB, 2002 [204]

Compounds with combined SRI activity and NK1 UCB, 2002 [205]

Concurrent administration of an SRI and a GABA-B antagonist Lundbeck, 2004 [206]

Concurrent administration of an SRI and a GABA-A a 2/3 agonist Pfizer, 2002 [207]

Concurrent administration of an SRI and a GABA-A a 2/3 agonist MSD, 1999 [208]

Compound with combined SRI activity and MC4 receptors antagonism Taisho Pharmaceutical Co, 2005 [209]

Concurrent administration of an SRI and N-acetylcysteine Yale University, 2006 [210]

Concurrent administration of SRI and 5-hydroxytryptophan Duke University, 2005 [211]

Concurrent administration of an SRI and an imidazoline I2 agonist or compounds with combined activity Merck KgaA, 2005 [212]

Concurrent administration of an SRI and Mecamylamine Yale University, 2005 [213]

Concurrent administration of an SRI and Loxapine Lundbeck, 2005 [214]

Concurrent administration of an SRI and a glycine type 1 (GlyT-1) inhibitor Lundbeck, 2005 [215]

Concurrent administration of an SRI and Agomelatine Lundbeck, 2005 [216]

Concurrent administration of an SRI and Alverine Cerep, 2005 [217]

Concurrent administration of an SRI and an NMDA antagonist Forrest Labs, 2005 [218]

Concurrent administration of an SRI and Gaboxadol Lundbeck, 2004 [219]

Concurrent administration of an SRI and a nitric oxide synthase inhibitor National University of Ireland, 2004 [220]

Concurrent administration of an SRI and Modafinil Emory University, 2004 [221]


(Table 5) Contd.

Combination for treatment of depression Reference

Compounds with combined SRI activity and acetylcholinesterase inhibition Sankyo, 2002 [222]

Concurrent administration of an SRI and a sigma ligand Pfizer, 2002 [223]

Concurrent administration of an SRI and an estrogenic agent American Home Products, 2002 [224]

Concurrent administration of an SRI and Lithium University Prilly-Lausanne, 2001 [225]

Concurrent administration of an SRI and Lithium Free University of Berlin, 1995 [226]

Concurrent administration of an SRI and Buspirone University of Helsinki, 2001 [227]

Concurrent administration of an SRI, Buspirone and Pindolol Sanofi, 2000 [67]

Concurrent administration of an SRI and Buspirone University of Thessaloniki, 1998 [99]

Concurrent administration of an SRI and a betablocker SKB, 1999 [66]

Concurrent administration of an SRI and a 5-HT4 agonist McGill University, 2006 [228]

Concurrent administration of an SRI and Triiodothyronine Harvard University, 2005 [229]

This does not in any way mean that the importance ofserotonin reuptake inhibition in treatment of depression willbe less in the future. As illustrated in this review, a numberof SRI enhancing strategies have been attempted, and thepossibilities are far from exhausted.

The ASRIs with action on the allosteric site might wellbe a new class of efficient antidepressants, Escitaloprambeing the first example. Major efforts have been put into theSERT/5-HT1A combination, but for various reasons the firstdrugable compound of this class remains to be found, soclinical validation of this concept is still pending. Interest forrelated combinations like SERT/5-HT1B/1D has also beenminimal in recent years, although this combination mighthold some promise. The new, potent SERT/NET comp-ounds, eg Duloxetine, are now on the market, and time willshow whether they constitute an improved therapy. It will beinteresting to follow compounds with a SERT/NET/DATprofile, since the DAT component if tolerated - mightresolve some of the key features of depression not addressedby the SSRIs.

A number of relatively unexplored combinationsdefinitely warrant further studies. The importance of a 2antagonism for antidepressant action has long been known asin eg Mirtazapine. However, only very few attempts offinding SERT/a 2 active compounds have been reported sofar. Similarly, SERT combinations with 5-HT2A or 5-HT2C aswell as GABA-A/GABA-B are also opportunities thatshould be further explored.

Although a large number of other types of targets arebeing pursued in the search for better antidepressants andalthough the future will bring a much deeper understandingof the disease biology of depression, there is no doubt in ourminds that serotonin reuptake inhibition will continue to playa major role in this disease area for many years to come.

ACKNOWLEDGEMENTS

We thank Drs Jrn Arnt and Sandra Hogg Willigers, H.Lundbeck A/S, for their valuable input and suggestions in

the preparation of this manuscript. We also thank ExecutiveSecretary Vibeke Vips Bekker for editorial assistance.

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